U.S. patent number 7,479,489 [Application Number 11/208,962] was granted by the patent office on 2009-01-20 for heterocyclic antiviral compounds.
This patent grant is currently assigned to Roche Palo Alto LLC. Invention is credited to James F. Blake, Jay Bradford Fell, John P. Fischer, Robert Than Hendricks, John E. Robinson, Stacey Renee Spencer, Peter J. Stengel.
United States Patent |
7,479,489 |
Blake , et al. |
January 20, 2009 |
Heterocyclic antiviral compounds
Abstract
Compounds having the formula I wherein A, m and R.sup.1 are
herein defined are Hepatitis C virus polymerase inhibitors. Also
disclosed are compositions and methods for treating diseases
mediated by HCV and for inhibiting hepatitis replication. Also
disclosed are processes for making the compounds and synthetic
intermediates used in the process ##STR00001##
Inventors: |
Blake; James F. (Longmont,
CO), Fell; Jay Bradford (Longmont, CO), Fischer; John
P. (Longmont, CO), Hendricks; Robert Than (San Carlos,
CA), Robinson; John E. (Commerce City, CO), Spencer;
Stacey Renee (Lyons, CO), Stengel; Peter J. (Longmont,
CO) |
Assignee: |
Roche Palo Alto LLC (Palo Alto,
CA)
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Family
ID: |
35180855 |
Appl.
No.: |
11/208,962 |
Filed: |
August 22, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20060040927 A1 |
Feb 23, 2006 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60677710 |
May 4, 2005 |
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60603771 |
Aug 23, 2004 |
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Current U.S.
Class: |
514/224.2;
544/52 |
Current CPC
Class: |
C07D
413/06 (20130101); A61P 43/00 (20180101); C07D
471/04 (20130101); A61P 31/14 (20180101); C07D
417/04 (20130101); C07D 495/04 (20130101) |
Current International
Class: |
C07D
417/02 (20060101); A61K 31/5415 (20060101) |
Field of
Search: |
;544/52 ;514/224.2 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 00/55147 |
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Sep 2000 |
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WO |
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WO 01/01933 |
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Jan 2001 |
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WO |
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WO 01/85172 |
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Nov 2001 |
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WO |
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WO 02/098424 |
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Dec 2002 |
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WO |
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WO 03/037262 |
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May 2003 |
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WO |
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WO 03/059356 |
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Jul 2003 |
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WO |
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WO 03/099801 |
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Dec 2003 |
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WO |
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WO 2004/041818 |
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May 2004 |
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WO |
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WO 2004/052312 |
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Jun 2004 |
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WO |
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WO 2004/052313 |
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Jun 2004 |
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WO |
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WO 2004/058150 |
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Jul 2004 |
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WO |
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WO 2005/019191 |
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Mar 2005 |
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WO |
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Other References
TT. Nguyen et al., Resistance profile of a hepatitis C Virus
RNA-dependent RNA polymerase benzothiadiazine inhibitor Antimicrob.
Agents and Chemother. 2003 47(11)3525-30. cited by other .
B. Gu et al., "Arresting Initiation of Hepatitis C. Virus RNA
synthesis using heterocyclic derivatives" J. Biol. Chem. 2003
278(19): 16602-16607. cited by other .
D. Dhanak et al., "Identification and Biological Characterization
of Heterocyclic Inhibitors of HCV RNA-dependent RNA polymerase" J.
Biol. Chem. 2002 277(41):38322-38327. cited by other.
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Primary Examiner: Habte; Kahsay T
Attorney, Agent or Firm: Buckwalter; Brian L.
Parent Case Text
CROSS RFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Ser. No.
60/603,771 filed Aug. 23, 2004 and to U.S. Ser. No. 60/677,710
filed May 4, 2005 which are hereby incorporated by reference in
their entirety.
Claims
We claim:
1. A compound according to formula I ##STR00043## ##STR00044##
wherein: A is selected from the grouping consisting of A-1, A-2,
A-3, A-4, A-5, A-6, A-7 and A-8; X is CH or N; X.sup.6 is --O--,
--NR.sup.6-- or X.sup.6 is absent; R.sup.1 in each incidence is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-6 alkoxy, optionally
substituted phenyl, optionally substituted phenyl-C.sub.1-6 alkyl,
C.sub.1-6hydroxyalkyl, C.sub.1-3 alkoxy-C.sub.1-6 alkyl, optionally
substituted phenoxy, optionally substituted phenyl-C.sub.1-3
alkoxy, C.sub.1-6 heteroalkoxy, hydroxyl, halogen
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --X.sup.5C(.dbd.O)R.sup.9,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b', --CO.sub.2R.sup.6,
X.sup.4NR.sup.aR.sup.b, nitro, and cyano wherein said optionally
substituted phenyl groups are substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3
alkoxy, phenoxy, C.sub.1-3 haloalkyl, hydroxy, halogen,
NR.sup.aR.sup.b, cyano and nitro; R.sup.2 is independently selected
from the group consisting of C.sub.1-6 alkyl, C.sub.3-6 alkenyl,
C.sub.3-6 alkynyl, pyridinylmethyl, imidazolinylmethyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl, C.sub.1-6
heteroalkyl and phenyl-C.sub.1-3 alkyl said phenyl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-3 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, phenoxy, C.sub.1-3 haloalkyl,
hydroxy, halogen, NR.sup.aR.sup.b, cyano and nitro; R.sup.3 in each
incidence is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4alkyl, C.sub.1-6 alkoxy,
halogen, R.sup.4 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4alkyl, C.sub.1-6
heteroalkyl, phenyl or phenyl-C.sub.1-4 alkyl said phenyl
optionally substituted independently with one to three R.sup.3
radicals; R.sup.4 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4alkyl, C.sub.1-6
heteroalkyl, phenyl or phenyl-C.sub.1-4 alkyl said phenyl
optionally substituted independently with one to three R.sup.3
radicals; R.sup.5 is hydroxyl, C.sub.1-6 alkoxy, --NR.sup.aR.sup.b,
phenyl or C.sub.1-6 heteroalkoxy; R.sup.6 is hydrogen or C.sub.1-6
alkyl; R.sup.7 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkyl-C.sub.1-4 alkyl, --NR.sup.aR.sup.b,
--NR.sup.6(CH.sub.2).sub.p-phenyl, --NHBoc, C.sub.1-6 heteroalkyl,
--X.sup.2(CH.sub.2).sub.oCOR.sup.5, optionally substituted
isoxazole, phenyl or phenyl-C.sub.1-3 alkyl wherein said phenyl and
said isoxazole are each optionally substituted independently with
one to three C.sub.1-3 alkyl, C.sub.1-3 alkoxy, halogen, nitro or
cyano; R.sup.8 is R.sup.6 or C.sub.1-6 acyl; R.sup.9 is C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, phenyl, NR.sup.aR.sup.b or OR.sup.4
wherein R.sup.4 is not hydrogen and said phenyl is optionally
substituted with one to three R.sup.3 radicals; R.sup.10 is phenyl
or pyridinyl said phenyl and said pyridinyl are optionally
substituted with one to three substituents selected from the group
consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3
haloalkyl, halogen, NR.sup.aR.sup.b, cyano and nitro; R.sup.a and
R.sup.b are (i) independently hydrogen, C.sub.1-6 alkyl or
C.sub.1-6 heteroalkyl, or (ii) taken together are (CH.sub.2).sub.q,
--(CH.sub.2).sub.2OC(.dbd.O)-- or
(CH.sub.2).sub.2X.sup.3(CH.sub.2).sub.2; R.sup.a' and R.sup.b'
independently are (i) hydrogen, C.sub.1-6 alkyl or C.sub.1-6
heteroalkyl, or (ii) R.sup.a' is --SO.sub.2R.sup.4,
--SO.sub.2NR.sup.aR.sup.b or --COR.sup.9 and R.sup.b' is hydrogen;
or (iii) R.sup.a' and R.sup.b' taken together are (CH.sub.2).sub.q
or (CH.sub.2).sub.2X.sup.3(CH.sub.2).sub.2; X.sup.1 is O,
S(O).sub.p, C(.dbd.O) or NR.sup.6; X.sup.2 is NR.sup.6 or a bond;
X.sup.3 is --O--, C.dbd.O or NR.sup.8; X.sup.4 is X.sup.1 or a
bond; X.sup.5 is NR.sup.6 or O; m and n are independently zero to
three; o and r are independently one to six; p is zero to two; q is
four to seven; and, pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 wherein: A is A-1-A-5, A-7 or
A-8; X.sup.6 is absent; R.sup.1 in each incidence is independently
selected from the group consisting of halogen, nitro, cyano,
hydroxyl, benzyloxy, C.sub.1-3 alkoxy, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, amino, C.sub.1-3 alkylamino, C.sub.1-6 acylamino, C.sub.1-6
alkylsulfonylamino, C.sub.1-6 alkylsulfonyl-C.sub.1-3 alkylamino,
C.sub.3-7 cycloalkylsulfonylamino, amino-C.sub.1-3 alkyl, C.sub.1-3
alkylamino-C.sub.1-3 alkyl, phenylsulfonylamino,
benzylsulfonylamino, 3,5-dimethyl-isoxazol-4-yl-sulfonyl-amino,
--OCH.sub.2CONR.sup.cR.sup.d, O(CH.sub.2).sub.2CONR.sup.cR.sup.d
--OCH.sub.2CO.sub.2R.sup.c, --NHCONR.sup.c, NHCO.sub.2-tert-Bu, and
NHSO.sub.2NR.sup.eR.sup.f; wherein: R.sup.c and R.sup.d are
independently hydrogen or C.sub.1-3 alkyl; and R.sup.e and R.sup.f
are independently hydrogen, C.sub.1-3 alkyl or CO.sub.2-tert-Bu or
R.sup.e and R.sup.f together are (CH.sub.2).sub.4 and
(CH.sub.2).sub.2OC(.dbd.O); R.sup.2 is C.sub.1-6 alkyl, C.sub.1-3
alkyl-C.sub.3-7 cycloalkyl, pyridinylmethyl or phenyl-C.sub.1-3
alkyl said phenyl optionally substituted with one to three groups
independently selected from halogen, cyano, C.sub.1-6 alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6 alkoxy; R.sup.3 in each incidence is
independently selected in each incidence from the group consisting
of halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; m and n are
independently zero to two.
3. The compound according to claim 1 wherein A is A-1.
4. The compound according to claim 3 wherein: R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
--NR.sup.aR.sup.b, halogen, nitro, and hydroxyl; R.sup.2 is
C.sub.1-6 alkyl, optionally substituted phenyl-C.sub.1-4 alkyl or
C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl; R.sup.3 in each incidence is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.1-6 alkoxy, halogen, --NR.sup.aR.sup.b, C.sub.1-6
acylamino, NR.sup.6SO.sub.2R.sup.7, cyano and nitro; R.sup.7 is
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, NR.sup.aR.sup.b, optionally
substituted phenyl or phenyl C.sub.1-3 alkyl; X is CH; X.sup.6 is
absent; and, X.sup.1 is O.
5. The compound according to claim 4 wherein R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, nitro, --NR.sup.aR.sup.b, halogen and
hydroxyl.
6. A compound according to claim 4 wherein m is one or two and the
7 and/or the 8 positions is(are) substituted.
7. A compound according to claim 6 wherein R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, nitro, --NR.sup.aR.sup.b, halogen and
hydroxyl.
8. A compound of claim 6 wherein m is one and the 7-position is
substituted.
9. A compound according to claim 8 wherein R.sup.1 is iselected
from the group consisting of --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, halogen and hydroxyl, --NR.sup.aR.sup.b
and nitro.
10. A compound according to claim 9 wherein R.sup.1 is
NR.sup.6SO.sub.2R.sup.7, nitro or NR.sup.aR.sup.b.
11. The compound of claim 1 wherein A is A-3.
12. The compound according to claim 11 wherein: R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
halogen, nitro, --NR.sup.aR.sup.b and hydroxyl; R.sup.2 is
C.sub.1-6 alkyl, phenyl-C.sub.1-4 alkyl or C.sub.3-7
cycloalkyl-C.sub.1-4 alkyl; R.sup.7 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, NR.sup.aR.sup.b, optionally substituted phenyl or
phenyl C.sub.1-3 alkyl; X.sup.6 is absent; and, X.sup.1 is O.
13. A compound according to claim 12 wherein m is one or two and
the 7 and/or the 8 position(s) is(are) substituted.
14. A compound according to claim 13 wherein R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --NR.sup.aR.sup.b, nitro, halogen and
hydroxyl.
15. A compound according to claims 14 wherein m is one, the
7-position is substituted and R.sup.1 is nitro, NR.sup.aR.sup.b or
NR.sup.6SO.sub.2R.sup.7.
16. The compound according to claim 1 wherein A is A-2 and R.sup.10
is phenyl optionally substituted with one to three substituents
independently selected from the group consisting of C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, halogen,
NR.sup.aR.sup.b, cyano and nitro.
17. The compound according to claim 16 wherein: R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, halogen and hydroxyl; R.sup.2 is
C.sub.1-6 alkyl, phenyl-C.sub.1-4 alkyl or C.sub.3-7
cycloalkyl-C.sub.1-4 alkyl; X.sup.1 is O; and, X.sup.6 is
absent.
18. The compound according to claim 1 wherein A is A-4.
19. The compound according to claim 18 wherein: R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.aR.sup.b,
--X.sup.5C(.dbd.O)R.sup.9, halogen and hydroxyl; R.sup.2 is
C.sub.1-6 alkyl, phenyl-C.sub.1-4 alkyl or C.sub.3-7
cycloalkyl-C.sub.1-4 alkyl; and, X.sup.1 is O.
20. The compound according to claim 1 wherein A is A-5.
21. The compound according to claim 20 wherein: R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6COR.sup.5,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b, halogen, nitro, or hydroxyl; R.sup.2 is C.sub.1-6
alkyl, optionally substituted phenyl-C.sub.1-4 alkyl or C.sub.3-7
cycloalkyl-C.sub.1-4 alkyl; R.sup.3 is C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen, --NR.sup.aR.sup.b, C.sub.1-6 acylamino,
NR.sup.6SO.sub.2R.sup.7, cyano or nitro; X.sup.6 is absent; and,
X.sup.1 is O.
22. The compound according to claim 1 wherein A is A-6.
23. The compound according to claim 1 wherein A is A-7 or A-8.
24. The compound according to claim 23 wherein: R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
--NR.sup.aR.sup.b, halogen, nitro, and hydroxyl; R.sup.2 is
C.sub.1-6 alkyl, optionally substituted phenyl-C.sub.1-4 alkyl or
C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl; R.sup.7 is C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, NR.sup.aR.sup.b, optionally substituted
phenyl or phenyl C.sub.1-3 alkyl; X is CH; X.sup.6 is absent; and,
X.sup.1 is O.
25. The compound according to claim 24 wherein R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, nitro, --NR.sup.aR.sup.b, halogen and
hydroxyl.
26. A compound according to claim 24 wherein m is one or two and
the seven- and/or eight-positions is(are) substituted.
27. A compound according to claim 26 wherein R.sup.1 in each
incidence is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, nitro, --NR.sup.aR.sup.b, halogen and
hydroxyl.
28. A compound of claim 26 wherein m is one and the 7-position is
substituted.
29. A compound according to claim 28 wherein R.sup.1 is selected
from the group consisting of --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, halogen or hydroxyl, --NR.sup.aR.sup.b
and nitro.
30. A compound according to claim 29 wherein R.sup.1 is
NR.sup.6SO.sub.2R.sup.7, nitro or NR.sup.aR.sup.b.
31. A compound according to claim 1 wherein the compound is
selected from the group consisting of:
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-4-hydroxy-
-1-(3-methyl-butyl)-1H-quinolin-2-one;
1-(2-Cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-fluoro-4-hydroxy-1H-quinolin-2-one;
6-Chloro-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)--
4-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one;
1-(2-Cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-4-hydroxy-6-methyl-1H-quinolin-2-one;
1-(2-Cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-4-hydroxy-6-methoxy-1H-quinolin-2-one;
6-Chloro-1-(2-cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6--
benzo[1,4]thiazin-3-yl)-4-hydroxy-1H-quinolin-2-one;
3-(6-Chloro-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)--
4-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(2-fluo-
ro-benzyl)-4-hydroxy-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
ro-benzyl)-4-hydroxy-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-3-yl)-1-(4-fluoro-be-
nzyl)-4-hydroxy-1H-quinolin-2-one, sodium salt;
1-(2-Cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-4-hydroxy-1H-[1,8]naphthyridin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-4-hydroxy-
-1-(3-methyl-butyl)-1H-[1,8]naphthyridin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
4-hydroxy-1-(3-methyl-butyl)-1H-[1,8]naphthyridin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one, sodium salt;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
ro-benzyl)-4-hydroxy-6-methyl-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
ro-benzyl)-4-hydroxy-6-methyl-1H-quinolin-2-one, sodium salt;
1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-3-(7-nitro-1,1-dioxo-1,4-dihyd-
ro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one;
3-(6-Cyano-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-4-
-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one;
3-(6-Aminomethyl-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-
-yl)-4-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one;
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-hydroxy-1,1-dioxo-1,4-dihydro-
-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one;
3-(7-Benzyloxy-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-y-
l)-6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one;
2-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-aceta-
mide;
3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3--
yl)-1-(2-cyclopropyl-ethyl)-4-hydroxy-1H-quinolin-2-one;
3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-
-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-acetamid-
e;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methan-
esulfonamide;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methanes-
ulfonamide, sodium salt;
1-(3,4-Difluoro-benzyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-fluoro-4-hydroxy-1H-quinolin-2-one;
1-(3,4-Difluoro-benzyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-fluoro-4-hydroxy-1H-quinolin-2-one, sodium salt;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-1H-quinolin-2-one, sodium
salt;
3-[3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluo-
ro-4-hydroxy-2-oxo-2H-quinolin-1-ylmethyl]-benzonitrile;
3-[3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluo-
ro-4-hydroxy-2-oxo-2H-quinolin-1-ylmethyl]-benzonitrile, sodium
salt;
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-meth-
anesulfonamide;
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-meth-
anesulfonamide, sodium salt; Propane-1-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
Propane-1-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide,
sodium salt;
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methoxy-1,1-dioxo-1,4-dihydro-
-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one;
{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-acetic
acid methyl ester; Ethanesulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
Cyclopropanesulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
2-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-N,N-d-
imethyl-acetamide;
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-N-me-
thyl-methanesulfonamide; 3,5-Dimethyl-isoxazole-4-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-benz-
enesulfonamide;
1-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-3-me-
thyl-urea;
3-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihy-
dro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin--
7-yloxy}-propionamide;
N-{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-sulf-
amide (I-40); Pyrrolidine-1-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide
(I-65);
2-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-qu-
inolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylox-
y}-N-methyl-acetamide; Ethanesulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-[3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl)-1,1-dioxo-1,4-d-
ihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl]-methanesulfonamide;
N-{3-[1-(4-Fluoro-benzyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methanes-
ulfonamide; Propane-1-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-N-methyl-
-methanesulfonamide;
N-{3-[6-Fluoro-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-q-
uinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-methanesulfonamide;
N-{3-[1-(3-Chloro-4-fluoro-benzyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-q-
uinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-methanesulfonamide;
N-[3-(6-Fluoro-4-hydroxy-2-oxo-1-pyridin-3-ylmethyl-1,2-dihydro-quinolin--
3-yl)-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl]-methane-
sulfonamide;
N-[3-(1-Cyclohexylmethyl-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3--
yl)-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl]-methanesu-
lfonamide;
N-{3-[6-Fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-q-
uinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-methanesulfonamide; Cyclopropanesulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[1-(3,4-Difluoro-benzyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-meth-
anesulfonamide;
N-{3-[6-Fluoro-1-(4-fluoro-3-trifluoromethyl-benzyl)-4-hydroxy-2-oxo-1,2--
dihydro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thia-
zin-7-yl}-methanesulfonamide;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-C-phenyl-
-methanesulfonamide; 2-Oxo-oxazolidine-3-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[1-(4-Fluoro-benzyl)-4-hydroxy-6-methoxy-2-oxo-1,2-dihydro-quinolin--
3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methane-
sulfonamide;
N-{3-[6-Chloro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methanes-
ulfonamide; Propane-2-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
Butane-1-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[1-(4-Fluoro-benzyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-sulfamid-
e (I-64);
1-{3-[1-(4-Fluoro-benzyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-q-
uinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-3,3-dimethyl-sulfamide (I-62);
N-{3-[6,7-Difluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-meth-
anesulfonamide;
N-[3-(6-Fluoro-4-hydroxy-2-oxo-1-pyridin-4-ylmethyl-1,2-dihydro-quinolin--
3-yl)-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl]-methane-
sulfonamide; compound with trifluoro-acetic acid;
N-{3-[7-Chloro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-7-yl}-methanesulfon-
amide;
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methoxymethyl-1,1-dioxo-
-1,4-dihydro-1.lamda..sup.6benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one;
5-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-7-
-(4-fluoro-benzyl)-4-hydroxy-2-methyl-7H-thieno[2,3-b]pyridin-6-one;
N-{3-[7-(4-Fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-
-b]pyridin-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7--
yl}-methanesulfonamide;
N-{3-[7-(4-Fluoro-benzyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridi-
n-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-metha-
nesulfonamide;
(S)-5-tert-Butyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-4-hydroxy-1-(3-methyl-butyl)-1,5-dihydro-pyrrol-2-one;
(S)-5-Cyclohexyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-4-hydroxy-1-(3-methyl-butyl)-1,5-dihydro-pyrrol-2-one;
(S)-5-((S)-sec-Butyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]t-
hiazin-3-yl)-4-hydroxy-1-(3-methyl-butyl)-1,5-dihydro-pyrrol-2-one;
(S)-1-Benzyl-5-((S)-sec-butyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-be-
nzo[1,4]thiazin-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one;
(S)-3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4--
fluoro-benzyl)-4-hydroxy-5-isobutyl-1,5-dihydro-pyrrol-2-one;
(S)-5-Cyclohexyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one;
(S)-5-Cyclohexyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one;
sodium salt;
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihy-
dro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-
-7-yl}-methanesulfonamide;
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,5-d-
ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thia-
zin-7-yl}-methanesulfonamide;
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-3-methoxy-benzyl)-4-hydroxy-2-oxo-2,5--
dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thi-
azin-7-yl}-methanesulfohydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda-
..sup.6-benzo[1,4]thiazin-7-yl}-methanesulfonamide;
(S)-5-tert-Butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-nitro-1,1-dioxo-1,4-d-
ihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1,5-dihydro-pyrrol-2-one;
(S)-3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-y-
l)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one;
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-
-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-sulfamide (II-14);
(S)-3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-y-
l)-5-tert-butyl-1-(2-cyclopropyl-ethyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one-
;
N-{3-[(S)-5-tert-Butyl-1-(2-cyclopropyl-ethyl)-4-hydroxy-2-oxo-2,5-dihyd-
ro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin--
7-yl}-methanesulfonamide;
1-tert-Butyl-4-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3--
yl)-2-(4-fluoro-benzyl)-5-hydroxy-1,2-dihydro-pyrazol-3-one;
N-{3-[4-(4-fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridi-
n-6-yl]-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-7-yl}-methanesul-
fonamide; and,
N-{3-[2-Ethyl-7-(4-fluoro-benzyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3--
b]pyridin-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-7-yl}-me-
thanesulfonamide.
32. A method for treating a disease caused by Hepatitis C Virus
(HCV) infection comprising administering to a patient in need
thereof, a therapeutically effective quantity of a compound
according to claim 1.
33. The method of claim 32 wherein A in the compound of formula I
is A-1, A-7 or A-8.
34. The method of claim 33 wherein A in the compound of formula I
is A-3.
35. The method of claim 34 further comprising administering at
least one immune system modulator which immune system modulator is
an interferon, interleukin, tumor necrosis factor or colony
stimulating factor and/or at least one antiviral agent which
antiviral agent is HCV protease inhibitor, another HCV polymerase
inhibitor, a HCV helicase, HCV primase inhibitor or a HCV fusion
inhibitor or ribavirin.
36. The method of claim 35 wherein the immune system modulator is
an interferon-.alpha.2a or interferon-.alpha.2b or an
interferon-.alpha.2a or interferon-.alpha.2b covalently derivatized
with polyethyleneglycol (PEG).
37. The method of claim 35 comprising administering ribavirin, an
HCV protease inhibitor, or another HCV polymerase inhibitor.
38. The method of claim 35 wherein the antiviral compound is
selected from the group consisting of an a HCV helicase, HCV
primase inhibitor or a HCV fusion inhibitor.
39. A pharmaceutical composition comprising a therapeutically
effective quantity of a compound according to claim 1 admixed with
at least one pharmaceutically acceptable carrier, diluent or
excipient.
40. A process for preparing a compound according to claim 1 wherein
A is A-1, A-2 or A-7 comprising the steps of: (i) contacting an
optionally substituted
(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-acetic
acid alkyl ester with a base whose pK.sub.b is sufficiently great
to abstract a proton under conditions sufficient to convert V to
the corresponding conjugate base Va; ##STR00045## (ii) contacting
Va with an optionally ring fused
3-substituted-3H-[1,3]-oxazine-2,6-dione VI under conditions
sufficient to result in condensation with Va and cyclization to
afford VII ##STR00046##
41. A process for preparing a compound according to claim 1 wherein
A is A-3 comprising the steps of: (i) contacting an optionally
substituted
(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-acetic
acid derivative V wherein R is OH, Cl, O--C.sub.1-6 alkyl with an
amino acid ester VIII wherein R'' is C.sub.1-6 alkyl, and R.sup.1,
R.sup.2 and R.sup.4 are as defined in claim 1 under conditions
sufficient to promote amide bond formation; ##STR00047## (ii)
contacting IX with a base whose pK.sub.b is sufficient to abstract
a proton from the methylene linked to the thiazine ring under
conditions sufficient to convert IX to the corresponding conjugate
base and induce intra-molecular cyclization to produce X
##STR00048##
Description
FIELD OF THE INVENTION
The present invention provides non-nucleoside compounds and certain
derivatives thereof which are inhibitors of RNA-dependent RNA viral
polymerase. These compounds are inhibitors of RNA-dependent RNA
viral replication and are useful for the treatment of RNA-dependent
RNA viral infection. They are particularly useful as inhibitors of
hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV
replication, and for the treatment of hepatitis C infection.
BACKGROUND
The invention relates to non-nucleoside derivatives as inhibitors
of HCV replicon RNA replication. In particular, the invention is
concerned with the use of heterocyclic compounds as inhibitors of
subgenomic HCV RNA replication and pharmaceutical compositions
containing such compounds.
Hepatitis C virus is the leading cause of chronic liver disease
throughout the world. (Boyer, N. et al. J. Hepatol. 2000
32:98-112). Patients infected with HCV are at risk of developing
cirrhosis of the liver and subsequent hepatocellular carcinoma and
hence HCV is the major indication for liver transplantation.
HCV has been classified as a member of the virus family
Flaviviridae that includes the genera flaviviruses, pestiviruses,
and hapaceiviruses which includes hepatitis C viruses (Rice, C. M.,
Flaviviridae: The viruses and their replication. In: Fields
Virology, Editors: B. N. Fields, D. M. Knipe and P. M. Howley,
Lippincott-Raven Publishers, Philadelphia, Pa., Chapter 30,
931-959, 1996). HCV is an enveloped virus containing a
positive-sense single-stranded RNA genome of approximately 9.4 kb.
The viral genome consists of a 5' untranslated region (UTR), a long
open reading frame encoding a polyprotein precursor of
approximately 3011 amino acids, and a short 3' UTR. The 5' UTR is
the most highly conserved part of the HCV genome and is important
for the initiation and control of polyprotein translation.
Genetic analysis of HCV has identified six main genotypes which
diverge by over 30% of the DNA sequence. More than 30 subtypes have
been distinguished. In the US approximately 70% of infected
individuals have Type 1a and 1b infection. Type 1b is the most
prevalent subtype in Asia. (X. Forns and J. Bukl, Clinics in Liver
Disease 1999 3:693-716; J. Bukh et al., Semin. Liv. Dis. 1995
15:41-63). Unfortunately Type 1 infectious is more resistant to
therapy than either type 2 or 3 genotypes (N. N. Zein, Clin.
Microbiol. Rev., 2000 13:223-235).
Viral structural proteins include a nucleocapsid core protein (C)
and two envelope glycoproteins, E1 and E2. HCV also encodes two
proteases, a zinc-dependent metalloproteinase encoded by the
NS2-NS3 region and a serine protease encoded in the NS3 region.
These proteases are required for cleavage of specific regions of
the precursor polyprotein into mature peptides. The carboxyl half
of nonstructural protein 5, NS5B, contains the RNA-dependent RNA
polymerase. The function of the remaining nonstructural proteins,
NS4A and NS4B, and that of NS5A (the amino-terminal half of
nonstructural protein 5) remain unknown. It is believed that most
of the non-structural proteins encoded by the HCV RNA genome are
involved in RNA replication
Currently there are a limited number of approved therapies are
currently available for the treatment of HCV infection. New and
existing therapeutic approaches to treating HCV and inhibition of
HCV NS5B polymerase have been reviewed: R. G. Gish, Sem. Liver.
Dis., 1999 19:5; Di Besceglie, A. M. and Bacon, B. R., Scientific
American, October: 1999 80-85; G. Lake-Bakaar, Current and Future
Therapy for Chronic Hepatitis C Virus Liver Disease, Curr. Drug
Targ. Infect Dis. 2003 3(3):247-253; P. Hoffmann et al., Recent
patents on experimental therapy for hepatitis C virus infection
(1999-2002), Exp. Opin. Ther. Patents 2003 13(11):1707-1723; M. P.
Walker et al., Promising Candidates for the treatment of chronic
hepatitis C, Exp. Opin. investing. Drugs 2003 12(8):1269-1280;
S.-L. Tan et al., Hepatitis C Therapeutics: Current Status and
Emerging Strategies, Nature Rev. Drug Discov. 2002 1:867-881; J. Z.
Wu and Z. Hong, Targeting NS5B RNA-Dependent RNA Polymerase for
Anti-HCV Chemotherapy, Curr. Drug Targ.--Infect. Dis. 2003
3(3):207-219.
Ribavirin
(1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-fura-
n-2-yl)-1H-[1,2,4]triazole-3-carboxylic acid amide; Virazole.RTM.)
is a synthetic, non-interferon-inducing, broad spectrum antiviral
nucleoside analog. Ribavirin has in vitro activity against several
DNA and RNA viruses including Flaviviridae (Gary L. Davis.
Gastroenterology 2000 118:S104-S114). Although, in monotherapy
ribavirin reduces serum amino transferase levels to normal in 40%
or patients, it does not lower serum levels of HCV-RNA. Ribavirin
also exhibits significant toxicity and is known to induce anemia.
Viramidine is a ribavirin prodrug converted to in hepatocytes.
Interferons (IFNs) have been available for the treatment of chronic
hepatitis for nearly a decade. IFNs are glycoproteins produced by
immune cells in response to viral infection. Two distinct types of
interferon are recognized: Type 1 includes several interferon
alphas and one interferon .beta., type 2 includes interferon
.gamma.. Type 1 interferons are produced mainly by infected cells
and protect neighboring cells from de novo infection. IFNs inhibit
viral replication of many viruses, including HCV, and when used as
the sole treatment for hepatitis C infection, IFN suppresses serum
HCV-RNA to undetectable levels. Additionally, IFN normalizes serum
amino transferase levels. Unfortunately, the effects of IFN are
temporary. Cessation of therapy results in a 70% relapse rate and
only 10-15% exhibit a sustained virological response with normal
serum alanine transferase levels. (Davis, Luke-Bakaar, supra)
One limitation of early IFN therapy was rapid clearance of the
protein from the blood. Chemical derivatization of IFN with
polyethyleneglycol (PEG) has resulted in proteins with
substantially improved pharmacokinetic properties. PEGASYS.RTM. is
a conjugate interferon .alpha.-2a and a 40 kD branched mono-methoxy
PEG and PEG-INTRON.RTM. is a conjugate of interferon .alpha.-2b and
a 12 kD mono-methoxy PEG. (B. A. Luxon et al., Clin. Therap. 2002
24(9):13631383; A. Kozlowski and J. M. Harris, J. Control. Release,
2001 72:217-224).
Combination therapy of HCV with ribavirin and interferon-.alpha.
currently is the optimal therapy for HCV. Combining ribavirin and
PEG-IFN (infra) results in a sustained viral response in 54-56% of
patients. The SVR approaches 80% for type 2 and 3 HCV. (Walker,
supra) Unfortunately, combination therapy also produces side
effects which pose clinical challenges. Depression, flu-like
symptoms and skin reactions are associated with subcutaneous
IFN-.alpha. and hemolytic anemia is associated with sustained
treatment with ribavirin.
A number of potential molecular targets for drug development as
anti-HCV therapeutics have now been identified including, but not
limited to, the NS2-NS3 autoprotease, the NS3 protease, the NS3
helicase and the NS5B polymerase. The RNA-dependent RNA polymerase
is absolutely essential for replication of the single-stranded,
positive sense, RNA genome. This enzyme has elicited significant
interest among medicinal chemists.
Nucleoside inhibitors can act either as a chain terminator or as a
competitive inhibitor that interferes with nucleotide binding to
the polymerase. To function as a chain terminator the nucleoside
analog must be taken up be the cell and converted in vivo to a
triphosphate to compete for the polymerase nucleotide binding site.
This conversion to the triphosphate is commonly mediated by
cellular kinases which imparts additional structural limitations on
any nucleoside. In addition this limits the direct evaluation of
nucleosides as inhibitors of HCV replication to cell-based
assays.
Non-nucleoside allosteric inhibitors of HIV reverse transcriptase
have proven effective therapeutics alone and in combination with
nucleoside inhibitors and with protease inhibitors. Several classes
of non-nucleoside HCV NS5B inhibitors have been described and are
currently at various stages of development including:
benzimidazoles, (H. Hashimoto et al. WO 01/47833, H. Hashimoto et
al. WO 03/000254, P. L. Beaulieu et al. WO 03/020240 A-2; P. L.
Beaulieu et al. U.S. Pat. No. 6,448,281 B1; P. L. Beaulieu et al.
WO 03/007945 A-1); indoles, (P. L. Beaulieu et al. WO 03/0010141
A-2); benzothiadiazines, e.g., 1, (D. Dhanak et al. WO 01/85172
A-1; D. Dhanak et al. WO 03/037262 A-2; K. J. Duffy et al.
WO03/099801 A-1, D. Chai et al. WO 2004052312, D. Chai et al.
WO2004052313, D. Chai et al. WO02/098424, J. K. Pratt et al. WO
2004/041818 A-1; J. K. Pratt et al. WO 2004/087577 A-1),
thiophenes, e.g., 2, (C. K. Chan et
##STR00002## al. WO 02/100851 A-2); benzothiophenes (D. C. Young
and T. R. Bailey WO 00/18231); P3-ketopyruvates (S. Attamura et al.
U.S. Pat. No. 6,492,423 B1, A. Attamura et al. WO 00/06529);
pyrimidines (C. Gardelli et al. WO 02/06246 A-1); pyrimidinediones
(T. R. Bailey and D. C. Young WO 00/13708); triazines (K.-H. Chung
et al. WO 02/079187 A-1); rhodanine derivatives (T. R. Bailey and
D. C. Young WO 00/10573, J. C. Jean et al. WO 01/77091 A-2);
2,4-dioxopyrans (R. A. Love et al. EP 256628 A-2); phenylalanine
derivatives (M. Wang et al. J. Biol. Chem. 2003 278:2489-2495).
SUMMARY OF THE INVENTION
The present invention is directed toward novel heterocyclic
compounds that inhibit HCV polymerase, methods of treating a
disorder mediated by HCV with said compounds and pharmaceutical
compositions containing said compound which compound possesses a
structure according to formula I
##STR00003## ##STR00004## wherein: A is selected from the grouping
consisting of A-1, A-2, A-3, A-4, A-5, A-6, A-7 and A-8; X is CH or
N; X.sup.6 is --O--, --NR.sup.6-- or X.sup.6 is absent; R.sup.1 in
each incidence is independently selected from the group consisting
of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-6 alkoxy,
optionally substituted phenyl, optionally substituted
phenyl-C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-3
alkoxy-C.sub.1-6 alkyl, optionally substituted phenoxy, optionally
substituted phenyl-C.sub.1-3 alkoxy, C.sub.1-6 heteroalkoxy,
hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --X.sup.5C(.dbd.O)R.sup.9,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b', --CO.sub.2R.sup.6,
X.sup.4NR.sup.aR.sup.b, nitro, and cyano wherein said optionally
substituted phenyl groups are substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3
alkoxy, phenoxy, C.sub.1-3 haloalkyl, hydroxy, halogen,
NR.sup.aR.sup.b, cyano and nitro; R.sup.2 is independently selected
from the group consisting of C.sub.1-6 alkyl, C.sub.3-6 alkenyl,
C.sub.3-6 alkynyl, pyridinylmethyl, imidazolinylmethyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl, C.sub.1-6
heteroalkyl and phenyl-C.sub.1-3 alkyl said phenyl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-3 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, phenoxy, C.sub.1-3 haloalkyl,
hydroxy, halogen, NR.sup.aR.sup.b, cyano and nitro; R.sup.3 in each
incidence is independently selected from the group consisting of
C.sub.1-16 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4alkyl, C.sub.1-6 alkoxy,
halogen, hydroxyl, --NR.sup.aR.sup.b, C.sub.1-6 acylamino,
--NR.sup.6SO.sub.2R.sup.7, cyano and nitro; R.sup.4 is hydrogen,
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkyl-C.sub.1-4alkyl, C.sub.1-6 heteroalkyl, phenyl or
phenyl-C.sub.1-4 alkyl said phenyl optionally substituted
independently with one to three R.sup.3 radicals; R.sup.5 is
hydroxyl, alkoxy, --NR.sup.aR.sup.b, phenyl or C.sub.1-6
heteroalkoxy; R.sup.6 is hydrogen or C.sub.1-6 alkyl; R.sup.7 is
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkyl-C.sub.1-4 alkyl, --NR.sup.aR.sup.b,
--NR.sup.6(CH.sub.2).sub.p-phenyl, --NHBoc, C.sub.1-6 heteroalkyl,
--X.sup.2(CH.sub.2).sub.oCOR.sup.5, optionally substituted
isoxazole, phenyl or phenyl-C.sub.1-3 alkyl wherein said phenyl and
said isoxazole are each optionally substituted independently with
one to three C.sub.1-3 alkyl, C.sub.1-3 alkoxy, halogen, nitro or
cyano; R.sup.8 is R.sup.6 or C.sub.1-6 acyl; R.sup.9 is C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, phenyl, NR.sup.aR.sup.b or OR.sup.4
wherein R.sup.4 is not hydrogen and said phenyl is optionally
substituted with one to three R.sup.3 radicals; R.sup.10 is phenyl
or pyridinyl said phenyl and said pyridinyl are optionally
substituted with one to three substituents selected from the group
consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3
haloalkyl, halogen, NR.sup.aR.sup.b, cyano and nitro; R.sup.a and
R.sup.b are (i) independently hydrogen, C.sub.1-6 alkyl or
C.sub.1-6 heteroalkyl, or (ii) taken together are (CH.sub.2).sub.q,
--(CH.sub.2).sub.2OC(.dbd.O)-- or
(CH.sub.2).sub.2X.sup.3(CH.sub.2).sub.2; R.sup.a' and R.sup.b'
independently are (i) hydrogen, C.sub.1-6 alkyl or C.sub.1-6
heteroalkyl, or (ii) R.sup.a is --SO.sub.2R.sup.4,
--SO.sub.2NR.sup.aR.sup.b or --COR.sup.9 and R.sup.b is hydrogen;
or (iii) R.sup.a' and R.sup.b' taken together are (CH.sub.2).sub.q
or (CH.sub.2).sub.2X.sup.3(CH.sub.2).sub.2; X.sup.1 is O,
S(O).sub.p, C(.dbd.O) or NR.sup.6; X.sup.2 is NR.sup.6 or a bond;
X.sup.3 is --O--, C.dbd.O or NR.sup.8; X.sup.4 is X.sup.1 or a
bond; X.sup.5 is NR.sup.6 or O; m and n are independently zero to
three; o and r are independently one to six; p is zero to two; q is
four to seven; and, pharmaceutically acceptable salts thereof.
The present invention is further directed a methods for inhibiting
HCV polymerase in cells infected by HCV.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention there is provided a
compound of formula I wherein A, X, X.sup.1-X.sup.6,
R.sup.1-R.sup.10, R.sup.a, R.sup.b, R.sup.a', R.sup.b', m, n, o, p,
q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1, A-2, A-3 or A-4; X is N,
CH, or CR.sup.3; X.sup.6 is absent; R.sup.1 is selected in each
incidence from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, optionally
substituted phenyl-C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl,
C.sub.1-3 alkoxy-C.sub.1-6 alkyl, optionally substituted phenoxy,
optionally substituted phenyl-C.sub.1-3 alkoxy, C.sub.1-6
heteroalkoxy, hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--NR.sup.6SO.sub.2R.sup.7, --X.sup.5C(.dbd.O)R.sup.9,
--X.sup.4(CH.sub.2).sub.rNR.sup.aR.sup.b, --CONR.sup.aR.sup.b,
nitro, and cyano wherein optionally substituted phenyl groups are
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, halogen, NR.sup.aR.sup.b, cyano and nitro;
R.sup.2 is C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl,
optionally substituted phenyl-C.sub.1-3 alkyl, cycloalkyl,
C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or C.sub.1-6 heteroalkyl;
R.sup.3 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, halogen, hydroxyl, --NR.sup.aR.sup.b, C.sub.1-6
acylamino, --NR.sup.6SO.sub.2R.sup.7, cyano or nitro; R.sup.4 is
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl or phenyl optionally
substituted independently with one to three R.sup.3 radicals;
R.sup.5 is hydroxyl, alkoxy, amino, --NR.sup.aR.sup.b, or C.sub.1-6
heteroalkoxy; R.sup.6 is hydrogen or C.sub.1-3 alkyl; R.sup.7 is
C.sub.1-6 alkyl, --NR.sup.aR.sup.b, C.sub.1-6 heteroalkyl,
--X.sup.2(CH.sub.2).sub.oCOR.sup.5, aryl C.sub.1-3 alkyl or phenyl
said phenyl optionally substituted with one to three radicals
independently selected in each incidence from C.sub.1-3 alkyl,
C.sub.1-3 alkoxy, halogen, nitro or cyano; R.sup.8 is R.sup.6 or
C.sub.1-6 acyl; R.sup.9 is C.sub.1-6 alkyl, NH.sub.2,
NR.sup.6R.sup.7, OH or OR.sup.7; R.sup.a and R.sup.b are (i)
independently hydrogen, C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl,
or (ii) taken together are (CH.sub.2).sub.q or
(CH.sub.2).sub.2X.sup.3(CH.sub.2).sub.2; X.sup.1 is O, S(O).sub.p
or NR.sup.6; X.sup.2 is NR.sup.6 or a bond; X.sup.3 is --O--,
C.dbd.O or NR.sup.8; X.sup.4 is X.sup.1 or a bond; X.sup.5 is
NR.sup.6 or O; m and n are independently zero to three; o is one to
six; p is zero to two; q is four to seven; r is zero to 6; and,
pharmaceutically acceptable salts thereof.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1-A-5 or A-7; X.sup.6 is
absent; R.sup.1 in each incidence is independently selected in each
incidence from the group consisting of halogen, nitro, cyano,
hydroxyl, benzyloxy, C.sub.1-3 alkoxy, amino, C.sub.1-3 alkylamino,
C.sub.1-6 acylamino, C.sub.1-6 alkylsulfonylamino, C.sub.1-6
alkylsulfonyl-C.sub.1-3 alkylamino-C.sub.3-7
cycloalkylsulfonylamino, amino-C.sub.1-3 alkyl, C.sub.1-3
alkylamino-C.sub.1-3 alkyl, phenylsulfonylamino,
benzylsulfonylamino, 3,5-dimethyl-4-isoxazol-4-yl-sulfonyl-amino,
--OCH.sub.2CONR.sup.cR.sup.d or O(CH.sub.2).sub.2CONR.sup.cR.sup.d
wherein R.sup.c and R.sup.d are independently hydrogen or C.sub.1-3
alkyl, --OCH.sub.2CO.sub.2R.sup.c wherein R.sup.c is as described
above, --NHCONR.sup.cR.sup.d, --NHCO.sub.2.sup.tBu, or
NHSO.sub.2NR.sup.eR.sup.f wherein R.sup.e and R.sup.f are
independently hydrogen, C.sub.1-3 alkyl or CO.sub.2-t-Boc, or
R.sup.e and R.sup.f together are (CH.sub.2).sub.4 and
(CH.sub.2).sub.2OC(.dbd.O); R.sup.2 is C.sub.1-6 alkyl, C.sub.1-3
alkyl-C.sub.3-7 cycloalkyl, pyridinylmethyl or aryl-C.sub.1-3 alkyl
said aryl optionally substituted with one to three groups
independently selected from halogen, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy; R.sup.3 in each incidence is independently
selected in each incidence from the group consisting of halogen,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or C.sub.1-6 alkoxy; and, m
and n are independently zero to two.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1; X, X.sup.1-X.sup.6,
R.sup.1-R.sup.3, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', m, n, o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1 X is CH; X.sup.1 is O;
X.sup.6 is absent; R.sup.1 in each incidence is independently
hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b or nitro; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl-C.sub.1-3 alkyl or optionally substituted
phenyl-C.sub.1-3 alkyl; R.sup.3 in each incidence is independently
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, --NR.sup.aR.sup.b,
C.sub.1-6 acylamino, NR.sup.6SO.sub.2R.sup.7, cyano or nitro; and
R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a', R.sup.b'
X.sup.2-X.sup.5, m, n, o, p, q and r are as defined
hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1; X is CH; X.sup.1 is O;
X.sup.6 is absent; R.sup.1 in each incidence is independently
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, nitro, NR.sup.aR.sup.b, halogen or
hydroxyl; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl-C.sub.1-3 alkyl or optionally substituted
phenyl-C.sub.1-3 alkyl; R.sup.3 in each incidence is independently
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, --NR.sup.aR.sup.b,
C.sub.1-6 acylamino, NR.sup.6SO.sub.2R.sup.7, cyano or nitro; and
R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a', R.sup.b'
X.sup.2-X.sup.5, m, n, o, p, q and r are as defined
hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1; X is CH; X.sup.1 is O;
X.sup.6 is absent; m is one or two and the seven- and/or
eight-positions are substituted; R.sup.1 in each incidence is
independently --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b, halogen, nitro, or hydroxyl; R.sup.2 is C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; R.sup.3 in each incidence is
independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen,
--NR.sup.aR.sup.b, C.sub.1-6 acylamino, NR.sup.6SO.sub.2R.sup.7,
cyano or nitro; and, X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', n, o, p, q and r are as defined herein
above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1; X is CH; X.sup.1 is O;
X.sup.6 is absent; m is one or two and the 7 and/or 8-positions
is(are) substituted; R.sup.1 in each incidence is independently
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, nitro, --NR.sup.aR.sup.b, halogen or
hydroxyl; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl-C.sub.1-3 alkyl or optionally substituted
phenyl-C.sub.1-3 alkyl; R.sup.3 in each incidence is independently
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, --NR.sup.aR.sup.b,
C.sub.1-6 acylamino, NR.sup.6SO.sub.2R.sup.7, cyano or nitro; and
X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b' n, o, p, q and r are as defined hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1; X is CH; X.sup.1 is O;
X.sup.6 is absent; m is one and the seven-position is substituted;
R.sup.1 is --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b, halogen, nitro, or hydroxyl; R.sup.2 is C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; R.sup.3 in each incidence is
independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen,
--NR.sup.aR.sup.b, C.sub.1-6 acylamino, NR.sup.6SO.sub.2R.sup.7,
cyano or nitro; and, X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', n, o, p, q and r are as defined herein
above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1; X is CH; X.sup.1 is O;
X.sup.6 is absent; m is one and the seven-position is substituted;
R.sup.1 is --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--NR.sup.6SO.sub.2R.sup.7, X.sup.4(CH.sub.2).sub.rNR.sup.aR.sup.b,
--X.sup.5C(.dbd.O)R.sup.9, nitro, NR.sup.aR.sup.b, halogen or
hydroxyl; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl-C.sub.1-3 alkyl or optionally substituted
phenyl-C.sub.1-3 alkyl; R.sup.3 in each incidence is independently
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, --NR.sup.aR.sup.b,
C.sub.1-6 acylamino, NR.sup.6SO.sub.2R.sup.7, cyano or nitro;
X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', n, o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-1; X is CH; X.sup.1 is O;
X.sup.6 is absent; m is one and the seven-position is substituted;
R.sup.1 is --NR.sup.6SO.sub.2R.sup.7, nitro, NR.sup.aR.sup.b;
R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or
optionally substituted phenyl-C.sub.1-3 alkyl; R.sup.3 in each
incidence is independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
halogen, --NR.sup.aR.sup.b, C.sub.1-6 acylamino,
NR.sup.6SO.sub.2R.sup.7, cyano or nitro; X.sup.2-X.sup.5,
R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a', R.sup.b', n, o, p, q
and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-3; X.sup.1-X.sup.6, R.sup.1,
R.sup.2, R.sup.4-R.sup.9, R.sup.a, R.sup.b, R.sup.a', R.sup.b', m,
o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-3; R.sup.1 in each incidence
is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6COR.sup.5,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b, halogen, nitro and hydroxyl; R.sup.2 is C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; X.sup.6 is absent; X.sup.1 is
O; X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', m, o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-3; R.sup.1 in each incidence
is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6COR.sup.5,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b, halogen, nitro and hydroxyl; R.sup.2 is C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; R.sup.4 is C.sub.1-6 alkyl or
C.sub.3-7 cycloalkyl; X.sup.6 is absent; X.sup.1 is O;
X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', m, o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-3; m is one or two and the
seven- and/or eight-position(s) is(are) substituted; R.sup.1 in
each incidence is independently selected from the group consisting
of --X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b, halogen, nitro, or hydroxyl; R.sup.2 is C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; X.sup.6 is absent; X.sup.1 is
O; X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-3; m is one or two and the
seven- and/or eight-position(s) is(are) substituted; R.sup.1 in
each incidednce is independently selected from the group consisting
of --X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, NR.sup.aR.sup.b, nitro, halogen or
hydroxyl; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl-C.sub.1-3 alkyl or optionally substituted
phenyl-C.sub.1-3 alkyl; X.sup.6 is absent; X.sup.1 is O;
X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-3; m is one, the
seven-position is substituted; R.sup.1 is
--NR.sup.6SO.sub.2R.sup.7, NR.sup.aR.sup.b or nitro; R.sup.2 is
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; X.sup.6 is absent; X.sup.1 is
O; X.sup.2-X.sup.5, R.sup.6-R.sup.9, R.sup.a, R.sup.b, o, p, q and
r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-2; R.sup.10 is phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-3 alkyl, C.sub.1-3
alkoxy, C.sub.1-3haloalkyl, halogen, NR.sup.aR.sup.b, cyano and
nitro; X.sup.1-X.sup.6, R.sup.1, R.sup.2, R.sup.5-R.sup.9, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', m, o, p, q and r are as defined herein
above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-2; R.sup.1 in each incidence
is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.aR.sup.b,
--X.sup.5C(.dbd.O)R.sup.9, NR.sup.aR.sup.b, nitro, halogen and
hydroxyl; R.sup.2 is C.sub.1-6 alkyl, phenyl-C.sub.1-4 alkyl or
C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl; R.sup.10 is phenyl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-13 alkyl, C.sub.1-13 alkoxy,
C.sub.1-3 haloalkyl, halogen, NR.sup.aR.sup.b, cyano and nitro;
X.sup.1 is O, and, X.sup.6 is absent; X.sup.2-X.sup.5,
R.sup.5-R.sup.9, R.sup.a, R.sup.b, m, o, p, q and r are as defined
hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-4; and, X.sup.1-X.sup.5,
R.sup.1, R.sup.2, R.sup.4-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', m, o, p, q and r are as defined hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-4; R.sup.1 in each incidence
is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, halogen and hydroxyl; R.sup.2 is
C.sub.1-6 alkyl, phenyl-C.sub.1-4 alkyl or C.sub.3-7
cycloalkyl-C.sub.1-4 alkyl; X.sup.1 is O; and X.sup.2-X.sup.5,
R.sup.4-R.sup.9, R.sup.a, R.sup.b, m, o, p, q and r are as defined
hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-5; and X.sup.1-X.sup.6,
R.sup.1-R.sup.3, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', m, n, o, p, q and r are as defined hereinabove
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-5; R.sup.1 in each incidence
is independently selected from the group consisting of
--X.sup.1(CH.sub.2).sub.oCOR.sup.5, --(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
X.sup.5C(.dbd.O)R.sup.9, CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b, halogen, nitro, and hydroxyl; R.sup.2 is C.sub.1-6
alkyl, optionally substituted aryl-C.sub.1-4 alkyl or C.sub.3-7
cycloalkyl-C.sub.1-4 alkyl; R.sup.3 is C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen, --NR.sup.aR.sup.b, C.sub.1-6 acylamino,
NR.sup.6SO.sub.2R.sup.7, cyano or nitro; X.sup.1 is O; X.sup.6 is
absent; and X.sup.2-X.sup.5, R.sup.5-R.sup.9, R.sup.a, R.sup.b,
R.sup.a', R.sup.b', m, n, o, p, q and r are as defined herein
above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-6; and, X.sup.1-X.sup.5,
R.sup.1, R.sup.2, R.sup.4-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', m, o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-7 or A-8; and,
X.sup.1-X.sup.5, R.sup.1, R.sup.2, R.sup.4-R.sup.9, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', m, o, p, q and r are as defined herein
above.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-7 or A-8; X.sup.1 is O;
X.sup.6 is absent; R.sup.1 in each incidence is independently
hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b or nitro; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl-C.sub.1-3 alkyl or optionally substituted
phenyl-C.sub.1-3 alkyl; and R.sup.5-R.sup.9, R.sup.a, R.sup.b,
R.sup.a', R.sup.b' X.sup.2-X.sup.5, m, o, p, q and r are as defined
hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-7 or A-8; X.sup.1 is O;
X.sup.6 is absent; R.sup.1 in each incidence is independently
hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --N.sup.aR.sup.b or nitro; R.sup.2 is
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; and R.sup.5-R.sup.9, R.sup.a,
R.sup.b, R.sup.a', R.sup.b' X.sup.2-X.sup.5, m, o, p, q and r are
as defined hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-7 or A-8; X.sup.1 is O;
X.sup.6 is absent; m is one or two and the seven- and/or
eight-position(s) is(are) substituted; R.sup.1 in each incidence is
independently hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b or nitro; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl-C.sub.1-3 alkyl or optionally substituted
phenyl-C.sub.1-3 alkyl; and R.sup.5-R.sup.9, R.sup.a, R.sup.b,
R.sup.a', R.sup.b' X.sup.2-X.sup.5, o, p, q and r are as defined
hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-7 or A-8; X.sup.1 is O;
X.sup.6 is absent; m is one or two and the seven- and/or
eight-position(s) is(are) substituted; R.sup.1 in each incidence is
independently hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --NR.sup.aR.sup.b or nitro; R.sup.2 is
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; and R.sup.5-R.sup.9, R.sup.a,
R.sup.b, R.sup.a', R.sup.b' X.sup.2-X.sup.5, o, p, q and r are as
defined hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-7 or A-8; X.sup.1 is O;
X.sup.6 is absent; m is one and the seven-position is substituted;
R.sup.1 is hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--(CH.sub.2).sub.oCOR.sup.5,
--X.sup.1(CH.sub.2).sub.oSO.sub.2R.sup.7,
--(CH.sub.2).sub.oSO.sub.2R.sup.7, --NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --CONR.sup.aR.sup.b, --CO.sub.2R.sup.6,
NR.sup.aR.sup.b or nitro; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl-C.sub.1-3 alkyl or optionally substituted
phenyl-C.sub.1-3 alkyl; and R.sup.5-R.sup.9, R.sup.a, R.sup.b,
R.sup.a', R.sup.b' X.sup.2-X.sup.5, o, p, q and r are as defined
hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-7 or A-8; X.sup.1 is O;
X.sup.6 is absent; m is one and the seven-position is substituted;
R.sup.1 is hydroxyl, halogen --X.sup.1(CH.sub.2).sub.oCOR.sup.5,
--NR.sup.6SO.sub.2R.sup.7,
--X.sup.4(CH.sub.2).sub.rNR.sup.a'R.sup.b',
--X.sup.5C(.dbd.O)R.sup.9, --NR.sup.aR.sup.b or nitro; R.sup.2 is
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or optionally
substituted phenyl-C.sub.1-3 alkyl; and R.sup.5-R.sup.9, R.sup.a,
R.sup.b, R.sup.a', R.sup.b' X.sup.2-X.sup.5, o, p, q and r are as
defined hereinabove.
In another embodiment of the present invention there is provided a
compound of formula I wherein A is A-7 or A-8; X.sup.1 is O;
X.sup.6 is absent; m is one and the seven-position is substituted;
R.sup.1 is --NR.sup.6SO.sub.2R.sup.7, --NR.sup.aR.sup.b or nitro;
R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl or
optionally substituted phenyl-C.sub.1-3 alkyl; and R.sup.5-R.sup.9,
R.sup.a, R.sup.b, R.sup.a', R.sup.b' X.sup.2-X.sup.5, o, p, q and r
are as defined hereinabove.
In another embodiment of the present invention there is provided a
compound selected from the following:
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-4-hydroxy-
-1-(3-methyl-butyl)-1H-quinolin-2-one;
1-(2-Cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-fluoro-4-hydroxy-1H-quinolin-2-one;
6-Chloro-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)--
4-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one;
1-(2-Cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-4-hydroxy-6-methyl-1H-quinolin-2-one;
1-(2-Cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-4-hydroxy-6-methoxy-1H-quinolin-2-one;
6-Chloro-1-(2-cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6--
benzo[1,4]thiazin-3-yl)-4-hydroxy-1H-quinolin-2-one;
3-(6-Chloro-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)--
4-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(2-fluo-
ro-benzyl)-4-hydroxy-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
ro-benzyl)-4-hydroxy-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
ro-benzyl)-4-hydroxy-1H-quinolin-2-one, sodium salt;
1-(2-Cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-4-hydroxy-1H-[1,8]naphthyridin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-4-hydroxy-
-1-(3-methyl-butyl)-1H-[1,8]naphthyridin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
4-hydroxy-1-(3-methyl-butyl)-1H-[1,8]naphthyridin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one, sodium salt;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
ro-benzyl)-4-hydroxy-6-methyl-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
ro-benzyl)-4-hydroxy-6-methyl-1H-quinolin-2-one, sodium salt;
1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-3-(7-nitro-1,1-dioxo-1,4-dihyd-
ro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one;
3-(6-Cyano-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-4-
-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one;
3-(6-Aminomethyl-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-
-yl)-4-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one;
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-hydroxy-1,1-dioxo-1,4-dihydro-
-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one;
3-(7-Benzyloxy-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-y-
l)-6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one;
2-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-aceta-
mide;
3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3--
yl)-1-(2-cyclopropyl-ethyl)-4-hydroxy-1H-quinolin-2-one;
3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-
-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-acetamid-
e;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methan-
esulfonamide;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methanes-
ulfonamide, sodium salt;
1-(3,4-Difluoro-benzyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-fluoro-4-hydroxy-1H-quinolin-2-one;
1-(3,4-Difluoro-benzyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-fluoro-4-hydroxy-1H-quinolin-2-one, sodium salt;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-1H-quinolin-2-one;
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-1H-quinolin-2-one, sodium
salt;
3-[3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluo-
ro-4-hydroxy-2-oxo-2H-quinolin-1-ylmethyl]-benzonitrile;
3-[3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluo-
ro-4-hydroxy-2-oxo-2H-quinolin-1-ylmethyl]-benzonitrile, sodium
salt;
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-meth-
anesulfonamide;
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-meth-
anesulfonamide, sodium salt; Propane-1-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
Propane-1-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide,
sodium salt;
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methoxy-1,1-dioxo-1,4-dihydro-
-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one;
{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-acetic
acid methyl ester; Ethanesulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
Cyclopropanesulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
2-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-N,N-d-
imethyl-acetamide;
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-N-me-
thyl-methanesulfonamide; 3,5-Dimethyl-isoxazole-4-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-benz-
enesulfonamide;
1-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-3-me-
thyl-urea;
3-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihy-
dro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin--
7-yloxy}-propionamide;
N-{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-sulf-
amide (I-40); Pyrrolidine-1-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide
(I-65);
2-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-qu-
inolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-ylox-
y}-N-methyl-acetamide; Ethanesulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-[3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl)-1,1-dioxo-1,4-d-
ihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl]-methanesulfonamide;
N-{3-[1-(4-Fluoro-benzyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methanes-
ulfonamide; Propane-1-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-N-methyl-
-methanesulfonamide;
N-{3-[6-Fluoro-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-q-
uinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-methanesulfonamide;
N-{3-[1-(3-Chloro-4-fluoro-benzyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-q-
uinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-methanesulfonamide;
N-[3-(6-Fluoro-4-hydroxy-2-oxo-1-pyridin-3-ylmethyl-1,2-dihydro-quinolin--
3-yl)-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl]-methane-
sulfonamide;
N-[3-(1-Cyclohexylmethyl-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3--
yl)-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl]-methanesu-
lfonamide;
N-{3-[6-Fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-q-
uinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-methanesulfonamide; Cyclopropanesulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[1-(3,4-Difluoro-benzyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-meth-
anesulfonamide;
N-{3-[6-Fluoro-1-(4-fluoro-3-trifluoromethyl-benzyl)-4-hydroxy-2-oxo-1,2--
dihydro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thia-
zin-7-yl}-methanesulfonamide;
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-C-phenyl-
-methanesulfonamide; 2-Oxo-oxazolidine-3-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[1-(4-Fluoro-benzyl)-4-hydroxy-6-methoxy-2-oxo-1,2-dihydro-quinolin--
3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methane-
sulfonamide;
N-{3-[6-Chloro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methanes-
ulfonamide; Propane-2-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
Butane-1-sulfonic acid
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide;
N-{3-[1-(4-Fluoro-benzyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-sulfamid-
e (I-64);
1-{3-[1-(4-Fluoro-benzyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-q-
uinolin-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-3,3-dimethyl-sulfamide (I-62);
N-{3-[6,7-Difluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-meth-
anesulfonamide;
N-[3-(6-Fluoro-4-hydroxy-2-oxo-1-pyridin-4-ylmethyl-1,2-dihydro-quinolin--
3-yl)-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl]-methane-
sulfonamide; compound with trifluoro-acetic acid;
N-{3-[7-Chloro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methanes-
ulfonamide;
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methoxymethyl-1,1-dioxo-1,4-d-
ihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one;
5-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-7-
-(4-fluoro-benzyl)-4-hydroxy-2-methyl-7H-thieno[2,3-b]pyridin-6-one;
N-{3-[7-(4-Fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-
-b]pyridin-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7--
yl}-methanesulfonamide;
N-{3-[7-(4-Fluoro-benzyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridi-
n-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-metha-
nesulfonamide;
(S)-5-tert-Butyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-4-hydroxy-1-(3-methyl-butyl)-1,5-dihydro-pyrrol-2-one;
(S)-5-Cyclohexyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-4-hydroxy-1-(3-methyl-butyl)-1,5-dihydro-pyrrol-2-one;
(S)-5-((S)-sec-Butyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]t-
hiazin-3-yl)-4-hydroxy-1-(3-methyl-butyl)-1,5-dihydro-pyrrol-2-one;
(S)-1-Benzyl-5-((S)-sec-butyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-be-
nzo[1,4]thiazin-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one;
(S)-3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4--
fluoro-benzyl)-4-hydroxy-5-isobutyl-1,5-dihydro-pyrrol-2-one;
(S)-5-Cyclohexyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one;
(S)-5-Cyclohexyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one;
sodium salt;
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihy-
dro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-
-7-yl}-methanesulfonamide;
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,5-d-
ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thia-
zin-7-yl}-methanesulfonamide;
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-3-methoxy-benzyl)-4-hydroxy-2-oxo-2,5--
dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thi-
azin-7-yl}-methanesulfonamide;
N-{3-[(S)-5-tert-Butyl-1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-d-
ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thia-
zin-7-yl}-methanesulfonamide;
(S)-5-tert-Butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-nitro-1,1-dioxo-1,4-d-
ihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1,5-dihydro-pyrrol-2-one;
(S)-3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-y-
l)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one;
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-
-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-
-sulfamide (II-14);
(S)-3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-y-
l)-5-tert-butyl-1-(2-cyclopropyl-ethyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one-
;
N-{3-[(S)-5-tert-Butyl-1-(2-cyclopropyl-ethyl)-4-hydroxy-2-oxo-2,5-dihyd-
ro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin--
7-yl}-methanesulfonamide;
1-tert-Butyl-4-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3--
yl)-2-(4-fluoro-benzyl)-5-hydroxy-1,2-dihydro-pyrazol-3-one;
N-{3-[4-(4-Fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridi-
n-6-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-metha-
nesulfonamide; or,
N-{3-[2-Ethyl-7-(4-fluoro-benzyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3--
b]pyridin-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-y-
l}-methanesulfonamide.
In another embodiment of the present invention there is provided a
method for treating a disease caused by the Hepatitis C Virus (HCV)
virus comprising administering to a patient in need thereof, a
therapeutically effective quantity of a compound according to
formula I wherein A, X, X.sup.1-X.sup.6, R.sup.1-R.sup.10, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', m, n, o, p, q and r are as defined
herein above.
In another embodiment of the present invention there is provided a
method for treating a disease caused by the Hepatitis C Virus (HCV)
virus comprising administering to a patient in need thereof, a
therapeutically effective quantity of a compound according to
formula I wherein A is A-1, A-7 or A-8 and X, X.sup.1-X.sup.6,
R.sup.1-R.sup.3, R.sup.5-R.sup.9, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', m, n, o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
method for treating a disease caused by the Hepatitis C Virus (HCV)
virus comprising administering to a patient in need thereof, a
therapeutically effective quantity of a compound according to
formula I wherein A is A-3, X, X.sup.1-X.sup.6, R.sup.1, R.sup.2,
R.sup.4-R.sup.9, R.sup.a, R.sup.b, R.sup.a', R.sup.b', m, o, p, q
and r are as defined herein above.
In another embodiment of the present invention there is provided a
method for treating a disease caused by the Hepatitis C Virus (HCV)
virus comprising administering to a patient in need thereof, a
therapeutically effective quantity of a compound according to
formula I wherein A, X, X.sup.1-X.sup.5, R.sup.1-R.sup.10, R.sup.a,
R.sup.b, m, n, o, p, q and r are as defined in claim 2.
In another embodiment of the present invention there is provided a
method for treating a disease caused by the Hepatitis C Virus (HCV)
virus co-comprising administering to a patient in need thereof, a
therapeutically effective quantity of a compound according to
formula I wherein A, X, X.sup.1-X.sup.6, R.sup.1-R.sup.10, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', m, n, o, p, q and r are as defined
herein above; and, at least one immune system modulator and/or at
least one antiviral agent that inhibits replication of HCV
In another embodiment of the present invention there is provided a
method for treating a disease caused by the Hepatitis C Virus (HCV)
virus co-comprising administering to a patient in need thereof, a
therapeutically effective quantity of a compound according to
formula I wherein A, X, X.sup.1-X.sup.6, R.sup.1-R.sup.10, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', m, n, o, p, q and r are as defined
herein above; and, an interferon, interleukin, tumor necrosis
factor or colony stimulating factor
In another embodiment of the present invention there is provided a
method for treating a disease caused by the Hepatitis C Virus (HCV)
virus co-comprising administering to a patient in need thereof, a
therapeutically effective quantity of a compound according to
formula I wherein A, X, X.sup.1-X.sup.6, R.sup.1-R.sup.10, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', m, n, o, p, q and r are as defined
herein above; and, an interferon or chemically derivatized
interferon.
In another embodiment of the present invention there is provided a
method for treating a disease caused by the Hepatitis C Virus (HCV)
virus co-comprising administering to a patient in need thereof, a
therapeutically effective quantity of a compound according to
formula I wherein A, X, X.sup.1-X.sup.6, R.sup.1-R.sup.10, R.sup.a,
R.sup.b, R.sup.a', R.sup.b', m, n, o, p, q and r are as defined
herein above; and an HCV protease inhibitor, another HCV polymerase
inhibitor, a HCV helicase inhibitor, a HCV primase inhibitor or a
HCV fusion inhibitor.
In another embodiment of the present invention there is provided a
method for inhibiting replication of the HCV virus comprising
exposing the virus to a compound according to formula I wherein A,
X, X.sup.1-X.sup.6, R.sup.1-R.sup.10, R.sup.a, R.sup.b, R.sup.a',
R.sup.b', m, n, o, p, q and r are as defined herein above.
In another embodiment of the present invention there is provided a
pharmaceutical composition for treating a disease caused by the HCV
comprising co-administering to a patient in need thereof, a
therapeutically effective quantity of a compound of formula I
wherein A, X, X.sup.1-X.sup.6, R.sup.1-R.sup.10, R.sup.a, R.sup.b,
R.sup.a', R.sup.b', m, n, o, p, q and r are as defined herein above
admixed with at least one pharmaceutically acceptable carrier,
diluent or excipient.
In another embodiment of the present invention there is provided a
pharmaceutical composition for treating a disease caused by the HCV
comprising co-administering to a patient in need thereof, a
therapeutically effective quantity of a compound of formula I
wherein A, X, X.sup.1-X.sup.5, R.sup.1-R.sup.10, R.sup.a, R.sup.b,
m, n, o, p, q and r are as defined in claim 2 admixed with at least
one pharmaceutically acceptable carrier, diluent or excipient.
Definitions
The phrase "a" or "an" entity as used herein refers to one or more
of that entity; for example, a compound refers to one or more
compounds or at least one compound. As such, the terms "a" (or
"an"), "one or more", and "at least one" can be used
interchangeably herein.
The phrase "as defined hereinabove" refers to the first definition
for each group as provided in the Summary of the Invention.
The terms "optional" or "optionally" as used herein means that a
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted phenyl" means that the phenyl may or may not be
substituted and that the description includes both unsubstituted
phenyl and phenyl wherein there is substitution.
It is contemplated that the definitions described herein may be
appended to form chemically-relevant combinations, such as
"heteroalkylaryl," "haloalkylheteroaryl," "arylalkylheterocyclyl,"
"alkylcarbonyl," "alkoxyalkyl," and the like.
Compounds of the present invention may have asymmetric centers
located on substituents linked to the heterocyclic scaffold that
produce enantiomers or diastereomers. All stereoisomers of
compounds of the instant invention are contemplated, either in
admixture or in pure or substantially pure form. The definition of
the compounds according to the invention embraces all both isolated
optical isomers enantiomers and their mixtures including the
racemic form. The pure optical isomer can be prepared by
stereospecific synthesis or by resolution of the racemic form by
physical methods, such as, for example, fractional crystallization
of diastereomeric salts, separation or crystallization of
diastereomeric derivatives or separation by chiral column
chromatography.
The term "alkyl" as used herein denotes an unbranched or branched
chain hydrocarbon residue containing 1 to 18 carbon atoms. The term
"lower alkyl" denotes an unbranched or branched chain hydrocarbon
residue containing 1 to 6 carbon atoms. Representative lower alkyl
groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl,
t-butyl or pentyl.
When the term "alkyl" is used as a suffix following another term,
as in "phenylalkyl," or "hydroxyalkyl," this is intended to refer
to an alkyl group, as defined above, being substituted with one to
two substituents selected from the other specifically-named group.
Thus, for example, "phenylalkyl" refers to an alkyl group having
one to two phenyl substituents, and thus includes benzyl,
phenylethyl, and biphenyl. An "alkylaminoalkyl" is an alkyl group
having one to two alkylamino substituents. "Hydroxyalkyl" includes
2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl,
2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl),
3-hydroxypropyl, and so forth. Accordingly, as used herein, the
term "hydroxyalkyl" is used to define a subset of heteroalkyl
groups defined below.
The term "alkylene" as used herein denotes a divalent saturated
linear hydrocarbon radical of 1 to 6 carbon atoms or a branched
saturated divalent hydrocarbon radical of 3 to 8 carbon atoms,
unless otherwise indicated. Examples of alkylene radicals include,
but are not limited to, methylene, ethylene, propylene,
2-methyl-propylene, butylene, and 2-ethylbutylene.
The term "acylamino" as used herein denotes a group of formula
--NHC(.dbd.O)R wherein R is hydrogen or lower alkyl as defined
herein
The terms "alkylsulfonylamino", "cycloalkylsulfonylamino" and
"arylsulfonylamino" as used herein denotes a group of formula
--NR'S(.dbd.O).sub.2R wherein R is alkyl, cycloalkyl or aryl
respectively, R' is hydrogen or C.sub.1-3 alkyl, and alkyl,
cycloalkyl and aryl are as defined herein.
The term "haloalkyl" as used herein denotes an unbranched or
branched chain alkyl group as defined above wherein 1, 2, 3 or more
hydrogen atoms are substituted by a halogen. Examples are
1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl,
trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl,
1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl,
2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl,
2,2-dichloroethyl, 3-bromopropyl and 2,2,2-trifluoroethyl. The term
"cycloalkyl" as used herein denotes a saturated carbocyclic ring
containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The term "cycloalkylalkyl" as used herein refers to the radical
R'R''--, wherein R' is a cycloalkyl radical as defined herein, and
R'' is an alkylene radical as defined herein with the understanding
that the attachment point of the cycloalkylalkyl moiety will be on
the alkylene radical. Examples of cycloalkylalkyl radicals include,
but are not limited to, cyclopropylmethyl, cyclohexylmethyl,
cyclopentylethyl. C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl refers to
the radical R'R'' where R' is C.sub.3-7 cyclolalkyl and R'' is
C.sub.1-3 alkylene as defined herein.
The term "alkenyl" as used herein denotes an unsubstituted or
substituted hydrocarbon chain radical having from 2 to 18 carbon
atoms, preferably from 2 to 4 carbon atoms, and having one or two
olefinic double bonds, preferably one olefinic double bond.
Examples are vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl
(crotyl).
The term "alkynyl" as used herein denotes an unsubstituted
hydrocarbon chain radical having from 2 to 18 carbon atoms,
preferably 2 to 4 carbon atoms, and having one or where possible
two triple bonds. Examples are ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl or 3-butynyl.
The term "alkoxy" as used herein denotes an unsubstituted
unbranched or branched chain alkyloxy group wherein the "alkyl"
portion is as defined above such as methoxy, ethoxy, n-propyloxy,
i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy,
hexyloxy, heptyloxy including their isomers. "Lower alkoxy" as used
herein denotes an alkoxy group with a "lower alkyl" group as
previously defined.
The term "alkylthio" or "thioalkyl" as used herein denotes an
unbranched or branched chain (alkyl)S-group wherein the "alkyl"
portion is as defined above. Examples are methylthio, ethylthio,
n-propylthio, i-propylthio, n-butylthio, i-butylthio or
t-butylthio.
The term "alkoxyalkyl" as used herein denotes an alkoxy group as
defined above which is bonded to an alkyl group as defined above.
Examples are methoxymethyl, methoxyethyl, methoxypropyl,
ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl,
methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl,
t-butyloxybutyl, methoxypentyl, ethoxypentyl, and propyloxypentyl
including their isomers.
The term "hydroxyalkyl" as used herein denotes an unbranched or
branched chain alkyl group as defined above wherein 1, 2, 3 or more
hydrogen atoms are substituted by a hydroxy group. Examples are
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl,
2-hydroxypropyl, 3-hydroxypropyl, hydroxyisopropyl, hydroxybutyl
and the like.
The term "heteroalkyl" as used herein means an alkyl radical as
defined herein wherein one, two or three hydrogen atoms have been
replaced with a substituent independently selected from the group
consisting of --OR.sup.a, --NR.sup.bR.sup.c, and
--S(O).sub.nR.sup.d (where n is an integer from 0 to 2), with the
understanding that the point of attachment of the heteroalkyl
radical is through a carbon atom, wherein R.sup.a is hydrogen,
acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R.sup.b and R.sup.c
are independently of each other hydrogen, acyl, alkyl, cycloalkyl,
or cycloalkylalkyl; and when n is 0, R.sup.d is hydrogen, alkyl,
cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R.sup.d is
alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, or
alkylamino. Representative examples include, but are not limited
to, 2-hydroxyethyl, 3-hydroxypropyl,
2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,
1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,
2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,
2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,
aminosulfonylpropyl, methylaminosulfonylmethyl,
methylaminosulfonylethyl, methylaminosulfonylpropyl, and the
like.
The term "heteroalkoxy" as used herein means an --O-(heteroalkyl)
group wherein heteroalkyl is defined herein. "C.sub.1-10
heteroalkoxy" as used herein refers to an --O-(heteroalkyl) wherein
heteroalkyl is C.sub.1-10. Representative examples include, but are
not limited to, 2-dimethylaminoethoxy and
3-sulfonamido-1-propoxy.
The term "aryl" as used herein denotes an optionally substituted
monocyclic or polycyclic-aromatic group comprising carbon and
hydrogen atoms. Examples of suitable aryl groups include, but are
not limited to, phenyl and naphthyl (e.g. 1-naphthyl or
2-naphthyl). Examples of suitable substituents for aryl include,
but are limited to, alkyl, alkenyl, alkynyl, aryloxy, cycloalkyl,
acyl, acylamino, alkoxy, amino, alkylamino, dialkylamino, halogen,
haloalkyl, hydroxy, nitro and cyano. The term "(het)aryl" or
"(hetero)aryl" refers to a denotes a moiety which can be either an
aryl group or a heteroaryl group.
The term "arylheteroalkyl" as used herein denotes the radical
R'R''-- wherein R' is an aryl radical as defined herein, and R'' is
a heteroalkylene radical. A heteroalkylene radical is alkylene
radical as defined herein wherein one, two or three hydrogen atoms
have been replaced with a substituent independently selected from
the group consisting of --OR.sup.a, --NR.sup.bR.sup.c, and
--S(O).sub.nR.sup.d wherein R.sup.a-R.sup.d are as defined for the
heteroalkyl group.
The term "sulfamide" as used herein refers to the sulfuric acid
diamide, RRNSO.sub.2NR'R' where R and R' are independently
selected. Thus, Et-NH--SO.sub.2--NH-Me would be designated
N-ethyl-N'-methylsulfamide or 1-ethyl-3-methyl sulfamide.
The terms pyridinylmethyl and imidazolinylmethyl as used herein
refer to substituents (i) and (ii), respectively.
##STR00005##
The term "isatoic anhydride" as used herein refers to a
3H-[1,3]oxazine-2,6-dione compound of formula (iii) wherein the 4
and 5 positions optionally are fused to an aryl or a heteroaryl
ring.
##STR00006##
The term "arylalkyl" or "aralkyl" as used herein denotes the
radical R'R''--, wherein R' is an aryl radical as defined herein,
and R'' is an alkylene radical as defined herein with the
understanding that the attachment point of the arylalkyl moiety
will be on the alkylene radical. Examples of arylalkyl radicals
include, but are not limited to, benzyl, phenylethyl,
3-phenylpropyl.
The term "aryloxy" as used herein denotes an O-aryl group, wherein
aryl is as defined above. An aryloxy group can be unsubstituted or
substituted with one or two suitable substituents. The term
"phenoxy" refers to an aryloxy group wherein the aryl moiety is a
phenyl ring.
The term "aryl-alkoxy" as used herein denotes alkoxy group as
defined herein wherein one hydrogen atom has been replaced with an
optionally substituted aryl substituents where aryl is as defined
herein.
The term "acyl" ("alkylcarbonyl") as used herein denotes a group of
formula C(.dbd.O)R wherein R is hydrogen, unbranched or branched
alkyl containing 1 to 7 carbon atoms or a phenyl group.
The term halogen stands for fluorine, chlorine, bromine or iodine,
preferably fluorine, chlorine, bromine.
The term "combination" as used herein in reference in administering
a plurality of drugs in a therapeutic regimen by concurrent or
sequential administration of the drugs at the same time or at
different times.
The term "chemically-derivatized interferon" as used herein refers
to an interferon molecule covalently linked to a polymer which
alters the physical and/or pharmacokinetic properties of the
interferon. A non-limiting list of such polymers include
polyalkylene oxide homopolymers such as polyethylene glycol (PEG)
or polypropylene glycol (PPG), polyoxyethylenated polyols,
copolymers thereof and block copolymers thereof, provided that the
water solubility of the block copolymers is maintained. One skilled
in the art will be aware of numerous approaches to linking the
polymer and interferon (for example, see A. Kozlowski and J. M.
Harris J. Control. Release 2001 72(1-3):217-24). A non-limiting
list of chemically derivatized IFN.alpha. contemplated in the
present patent includes peginterferon-.alpha.-2a (PEGASYS.RTM.) and
peginterferon-.alpha.-2b (PEGINTRON.RTM.).
Compounds of formula I exhibit tautomerism. Tautomeric compounds
can exist as two or more interconvertable species. Prototropic
tautomers result from the migration of a covalently bonded hydrogen
atom between two atoms. Tautomers generally exist in equilibrium
and attempts to isolate an individual tautomer usually produce a
mixture whose chemical and physical properties are consistent with
a mixture of compounds. The position of the equilibrium is
dependent on chemical features within the molecule. For example, in
many aliphatic aldehydes and ketones, such as acetaldehyde, the
keto form predominates while; in phenols, the enol form
predominates. Common prototropic tautomers include keto/enol
(--C(.dbd.O)--CH--.revreaction.--C(--OH).dbd.CH--), amide/imidic
acid (--C(.dbd.O)--NH--.revreaction.--C(--OH).dbd.N--) and amidine
(--C(.dbd.NR)--NH--.revreaction.--C(--NHR).dbd.N--) tautomers. The
latter two are particularly common in heteroaryl and heterocyclic
rings and the present invention encompasses all tautomeric forms of
the compounds. The thiazine ring I is capable of existing as a
tautomer Ia and the heterocyclic groups A.sup.1-A.sup.6 are capable
of existing in a tautomeric keto form.
##STR00007##
Compounds of formula I wherein A is CH.sub.2CO.sub.2R and R is
alkyl can exist in an additional tautomeric form corresponding to
(iv) and any reference to one of those tautomeric forms is made
with the intent that any of the interconvertable tautomeric forms
could be present.
The term "solvate" as used herein means a compound of the invention
or a salt, thereof, that further includes a stoichiometric or
non-stoichiometric amount of a solvent bound by non-covalent
intermolecular forces. Preferred solvents are volatile, non-toxic,
and/or acceptable for administration to humans in trace
amounts.
The term "hydrate" as used herein means a compound of the invention
or a salt thereof, that further includes a stoichiometric or
non-stoichiometric amount of water bound by non-covalent
intermolecular forces.
The term "clathrate" as used herein means a compound of the
invention or a salt thereof in the form of a crystal lattice that
contains spaces (e.g., channels) that have a guest molecule (e.g.),
a solvent or water) trapped within.
Abbreviations used in this application include: acetyl (Ac), acetic
acid (HOAc), azo-bis-isobutyrylnitrile (AIBN),
1-N-hydroxybenzotriazole (HOBT), atmospheres (Atm), high pressure
liquid chromatography (HPLC), 9-borabicyclo[3.3.1]nonane (9-BBN or
BBN), methyl (Me), tert-butoxycarbonyl (Boc), acetonitrile (MeCN),
di-tert-butyl pyrocarbonate or boc anhydride (BOC.sub.2O),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),
benzyl (Bn), m-chloroperbenzoic acid (MCPBA), butyl (Bu), methanol
(MeOH), benzyloxycarbonyl (cbz or Z), melting point (mp), carbonyl
diimidazole (CDI), MeSO.sub.2-- (mesyl or Ms),
1,4-diazabicyclo[2.2.2]octane (DABCO), mass spectrum (ms)
diethylaminosulfur trifluoride (DAST), methyl t-butyl ether (MTBE),
dibenzylideneacetone (Dba), N-carboxyanhydride (NCA),
N-methyl-morpholine (NMM), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
N-bromosuccinimide (NBS), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
N-methylpyrrolidone (NMP), 1,2-dichloroethane (DCE), pyridinium
dichromate (PDC), pyridinium chlorochromate (PCC),
N,N'-dicyclohexylcarbodiimide (DCC), dichloromethane (DCM), propyl
(Pr), diethyl azodicarboxylate (DEAD), phenyl (Ph),
di-iso-propylazodicarboxylate (DIAD), pounds per square inch (psi),
diethyl iso-propylamine (DIPEA), pyridine (pyr),
di-iso-butylaluminumhydride (DIBAL-H), room temperature (rt or RT),
N,N-dimethyl acetamide (DMA), tert-butyldimethylsilyl or
t-BuMe.sub.2Si (TBDMS), 4-N,N-dimethylaminopyridine (DMAP),
triethylamine (Et.sub.3N or TEA), N,N-dimethylformamide (DMF),
triflate or CF.sub.3SO.sub.2-- (Tf), dimethyl sulfoxide (DMSO),
trifluoroacetic acid (TFA), 1,1'-bis-(diphenylphosphino)ethane
(dppe), 2,2,6,6-tetramethylheptane-2,6-dione (TMHD),
1,1'-bis-(diphenylphosphino)ferrocene (dppf), thin layer
chromatography (TLC), ethyl acetate (EtOAc), tetrahydrofuran (THF),
diethyl ether (Et.sub.2O), trimethylsilyl or Me.sub.3Si (TMS),
ethyl (Et), p-toluenesulfonic acid monohydrate (TsOH or pTsOH),
lithium hexamethyl disilazane (LiHMDS),
4-Me-C.sub.6H.sub.4SO.sub.2-- or tosyl (Ts), iso-propyl (i-Pr),
N-urethane-N-carboxyanhydride (UNCA), ethanol (EtOH). Conventional
nomenclature including the prefixes normal (n), iso (i-), secondary
(sec-), tertiary (tert-) and neo have their customary meaning when
used with an alkyl moiety. (J. Rigaudy and D. P. Klesney,
Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press,
Oxford.).
Compounds and Preparation
Compounds of the present invention can be made by a variety of
methods depicted in the illustrative synthetic reaction schemes
shown and described below. The starting materials and reagents used
in preparing these compounds generally are either available from
commercial suppliers, such as Aldrich Chemical Co., or are prepared
by methods known to those skilled in the art following procedures
set forth in references such as Fieser and Fieser's Reagents for
Organic Synthesis; Wiley & Sons: New York, Volumes 1-21; R. C.
LaRock, Comprehensive Organic Transformations, 2.sup.nd edition
Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost
and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991;
Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W.
Rees (Eds) Pergamon, Oxford 1984, vol. 1-9; Comprehensive
Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds)
Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley
& Sons: New York, 1991, Volumes 1-40. The following synthetic
reaction schemes are merely illustrative of some methods by which
the compounds of the present invention can be synthesized, and
various modifications to these synthetic reaction schemes can be
made and will be recognized by one skilled in the art having
referred to the disclosure contained in this Application.
The starting materials and the intermediates of the synthetic
reaction schemes can be isolated and purified if desired using
conventional techniques, including but not limited to, filtration,
distillation, crystallization, chromatography, and the like. Such
materials can be characterized using conventional means, including
physical constants and including, but not limited to mass
spectrometry, nuclear magnetic resonance spectroscopy and infrared
spectroscopy.
Unless specified to the contrary, the reactions described herein
preferably are conducted under an inert atmosphere at atmospheric
pressure at a reaction temperature range of from about -78.degree.
C. to about 150.degree. C., more preferably from about 0.degree. C.
to about 125.degree. C., and most preferably and conveniently at
about room (or ambient) temperature, e.g., about 20.degree. C. One
skilled in the art will be able to identify optimal reaction
conditions for each transformation without undue
experimentation.
While the following schemes often depict specific compounds; the
reaction conditions are exemplary and can readily be adapted to
other reactants. Alternative conditions also are well known. The
reaction sequences in the following examples are not meant to limit
the scope of the invention as set forth in the claims.
Examples of representative compounds encompassed by the present
invention and within the scope of the invention are provided in the
following Tables. These examples and preparations which follow are
provided to enable those skilled in the art to more clearly
understand and to practice the present invention. They should not
be considered as limiting the scope of the invention, but merely as
being illustrative and representative thereof.
In general, the nomenclature used in this Application is based on
AUTONOM.TM. v.4.0, a Beilstein Institute computerized system for
the generation of IUPAC systematic nomenclature. If there is a
discrepancy between a depicted structure and a name given that
structure, the depicted structure is to be accorded more
weight.
##STR00008##
The preparation of 4-hydroxy-1-alkyl-3-aryl-1H-quinolin-2-ones by
condensation of isatoic acid anhydrides with aryl acetic esters was
reported by G. M. Coppola (Synth. Commun. 1985 15(2): 135-139). The
3-(1,1-dioxo-1,4-dihydro-benzo[1,4]thiazin-3-yl)-4-hydroxy-1H-quinolin-2--
one compounds 3 (see TABLE 1) of the present invention were
prepared by condensing an optionally substituted ethyl
[1,1-dioxo-1,4-dihydro-2H-benzo[1,4]thiazin-(3E)-ylidene]-acetate 4
with an (optionally substituted) isatoic anhydride 5 as depicted in
SCHEME 1. Esters other than ethyl esters can be used
interchangeably in the depicted schemes. Ethyl
(1,1-dioxo-1,4-dihydro-benzo[1,4]thiazin-3-yl)-acetate 4 was
prepared by alkylation and cyclization of 2-aminothiophenol (6) and
ethyl 3-chloroacetoacetate (7) to afford ethyl
[4H-benzo[1,4]thiazin-(3E)-ylidene]-acetate (8). The alkylation of
thiols and amines is optionally carried out in a solvent or mixture
of solvents such as DCM, DMF, PhH, toluene, chlorobenzene, THF,
PhH/THF, dioxane, MeCN or sulfolane with an alkylating agent such
as an alkyl 3-chloroacetoacetate, optionally in the presence of a
tertiary organic base or in the presence of an inorganic base,
conveniently at temperatures between 0 and 150.degree. C.,
preferably at temperatures between 0 and 100.degree. C. Cyclization
of the intermediate aminoketone cyclizes to affords 8. Protection
of the amine (8.fwdarw.9), oxidation of the sulfide to the
corresponding sulfone (9.fwdarw.10) and deprotection (10.fwdarw.11)
utilizing standard protocols affords 4. Ortho-aminothiopyridines
(M. H. Norman et al., J. Med. Chem. 1996, 39(24):4692-4703) afford
the corresponding compounds in which the thiazine is fused to a
pyridine moiety. Examples of 2-amino-thiophene-3-thiols are
depicted in Examples 20 and 21.
N-substituted isatoic anhydrides are available by alkylation of
isatoic anhydride or by cyclization of an N-substituted anthranilic
acid with phosgene or a phosgene equivalent. N-substituted
anthranilic acids can be prepared by displacement or coupling of
2-chlorobenzoic acid with amines or by reductive amination of
anthranilic acid (G. E. Hardtmann et al., J. Heterocyclic Chem.
1975 12:565). Aryl substituted isatoic acids are commercially
available or can be prepared from substituted anthranilic acid
derivatives. 1H-Pyrido[2,3-d][1,3]oxazine-2,4-diones useful for the
preparation of compounds of formula I-A-1 where X is nitrogen can
be prepared by known procedures (see, e.g., G. M. Coppola et al.,
J. Het. Chem. 1985 22:193-206, or D. J. LaCount and D. J. Dewsbury,
Synthesis 1982 972).
Some embodiments of the present invention are substituted on the
benzo[1,4]thiazinyl radical. Example 7 provides a method for
introducing a nitrogen-containing functional group onto the 5, 6, 7
or 8 positions of the ortho-phenylene moiety. The synthetic steps
parallel those depicted in SCHEME 1 to which is added a step that
introduces of 4-nitro substituent. One skilled in the art will
appreciate that substituted 2-amino-benzenethiols are available
from a variety of precursors which are useful for the preparation
of compounds of the present invention.
Ethyl
(7-Nitro-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-y-
l)-acetic acid (27d) is a particularly versatile synthetic
intermediate which can be prepared from 27a (example 7) via a
three-step sequence comprising protection of the secondary amino
contained in the thiazine ring, oxidation od the sulfur atom and
deprotection of the resulting sulfone. Examples of this sequence
are described in steps 2-4 of example 1.
There is considerable flexibility in the sequence of steps used to
prepare compounds of the present invention. For example, the
sequence depicted in example 7 introduces an
amino-methylsulfonamide substituent prior to formation of the
linkage between the thiazine and the hydroxyquinolone rings. The
linkage can also be introduced with thiazine 27d to afford a nitro
substituted compound which is a versatile advance intermediate for
the production of compounds of the present invention by reduction
of the nitro group and further elaboration of the resulting amine
(e.g. alkylation, acylation, sulfonylation and Michael addition,
see, e.g. example 20).
Similarly, example 6 illustrates the preparation of a 7-hydroxy
compound of the present invention. This sequence embarks from a
simple substituted aniline and introduces the requisite thiol via a
2-chloro-2.lamda..sup.4-benzo[1,2,3]dithiazole 19 which is
fragmented under basic reductive conditions to afford the
ortho-amino thiol which is cyclized without further isolation. The
reaction similarly affords a general route for introduction of one
or more substituents onto the
1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl
fragment. Further elaboration of the hydroxy group by alkylation of
the oxygen atom affords other compounds of the present
invention.
TABLE-US-00001 TABLE 1 (I-A-1) ##STR00009## No. R.sup.1 R.sup.2
R.sup.3 X Y ms mp I-1 H iso-amyl H CH H 410.49 411 I-2
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 426.47 427 188-189 I-3
H iso-amyl 6-Cl CH H 444.94 445 194-197 I-4 H
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-Me CH H 422.50 421 (M - H)
93-103 I-5 H --(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-OMe CH H 438.50
439 (MH) 220-221 I-6 H --(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-Cl CH
H 442.92 441 (M - H) 227-229 I-7 6-Cl iso-amyl H CH H 444.94 443 (M
- H) 90-110 I-8 H --CH.sub.2-o-C.sub.6H.sub.4F H CH H 448.47 449
(MH) >200 I-9 H --CH.sub.2-p-C.sub.6H.sub.4F H CH H 448.47 447
(M - H) 237-238 I-9a H --CH.sub.2-p-C.sub.6H.sub.4F H CH Na 470.46
447 (M - H) >250 I-10 H --(CH.sub.2).sub.2-c-C.sub.3H.sub.5 H N
H 409.46 410 (MH) I-11 H iso-amyl H N H 411.48 410 (M - H) I-12 H
iso-amyl 6-F N H 429.47 430 (MH) 90-112 I-13 H
--CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 466.46 465 (M - H) 233-2354
I-13a H --CH.sub.2-p-C.sub.6H.sub.4F 6-F CH Na 488.45 465 (M - H)
>250 I-14 H --CH.sub.2-p-C.sub.6H.sub.4F 6-Me CH H 462.50 461 (M
- H) 247-249 I-14a H --CH.sub.2-p-C.sub.6H.sub.4F 6-Me CH Na 484.48
461 (M - H) >250 I-15 7-NO.sub.2
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 471.63 I-16 6-CN
iso-amyl H CH H 435.50 434 (M - H) >250 I-17 6-CH.sub.2NH.sub.2
iso-amyl H CH H 439.53 440 (MH) I-18 7-OH
--CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 482.46 481 (M - H) 185.sup.1
I-19 7-OBn --CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 572.59 571 (M - H)
242-244 I-20 7-OCH.sub.2CONH.sub.2 --CH.sub.2-p-C.sub.6H.sub.4F 6-F
CH H 539.52 53- 8 (M - H) 145.sup.1 I-21 7-NH.sub.2
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 H CH H 423.49 424 (MH) >250
I-22 7-NH.sub.2 --CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 481.48 480 (M
- H) >250 I-23 7-NHAc --CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H
523.52 522 (M - H) >250 I-24 7-NHSO.sub.2Me
--CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 559.57 558 (M - H) >250
I-24a 7-NHSO.sub.2Me --CH.sub.2-p-C.sub.6H.sub.4F 6-F CH Na 581.55
558 (M - H) >250 I-25 H 3,4-di-F--C.sub.6H.sub.3CH.sub.2 6-F CH
H 484.46 483 (M - H) 230-235 I-25a H
3,4-di-F--C.sub.6H.sub.3CH.sub.2 6-F CH Na 506.44 483 (M - H)
230-235 I-26 H 3-Me-4-F--C.sub.6H.sub.3CH.sub.2 6-F CH H 480.49 479
(M - H) 225-230 I-26a H 3-Me-4-F--C.sub.6H.sub.3CH.sub.2 6-F CH Na
502.49 479 (M - H) >250 I-27 H 3-CN--C.sub.6H.sub.4CH.sub.2 6-F
CH H 473.48 474 (MH) >250 I-27a H 3-CN--C.sub.6H.sub.4CH.sub.2
6-F CH Na 495.47 474 (MH) >250 I-28 7-NHSO.sub.2Me
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 519.57 52- 0 (MH)
I-28a 7-NHSO.sub.2Me --(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH Na
541.56 - 520 (MH) >250 I-29 7-NHSO.sub.2-n-Pr
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 547.63- 548 (MH)
145-150 I-29a 7-NHSO.sub.2-n-Pr --(CH.sub.2).sub.2-c-C.sub.3H.sub.5
6-F CH Na 569.- 61 548 (MH) >250 I-30 7-OMe
--CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 496.49 497 (M - H) >250
I-31 7-OCH.sub.2CO.sub.2Me --CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H
554.53 55- 5 (MH) 200-207 I-32 7-NHSO.sub.2Et
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 533.60 53- 4 (MH)
140-142 I-33 7-NHSO.sub.2-c-C.sub.3H.sub.5
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F- CH H 545.61 546 (MH)
145-155 I-34 7-OCH.sub.2CONMe.sub.2 --CH.sub.2-p-C.sub.6H.sub.4F
6-F CH H 567.57 5- 66 (M - H) >250 I-35 7-N(Me)SO.sub.2Me
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 533.60- 208-212 I-36
##STR00010## --(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 600.65
150-157 I-37 7-NHSO.sub.2Ph --(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F
CH H 581.64 58- 2 (MH) >200 I-38 7-NHC(.dbd.O)NHMe
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 498.33- 499 (MH)
>220 I-39 7-O(CH.sub.2).sub.2CONH.sub.2
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F- CH H 513.54 514 (MH)
>250 I-40 7-NHSO.sub.2NH.sub.2
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 6-F CH H 520- .56 519 (M - H)
183-186 I-42 7-OCH.sub.2CONHMe --CH.sub.2-p-C.sub.6H.sub.4F 6-F CH
H 553.54 552 (M - H) >240 I-43 7-NHSO.sub.2Et
--CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 573.61 572 (M - H) I-44
7-NHSO.sub.2Me Me H CH H 447.49 448 (MH) I-45 7-NHSO.sub.2Me
--CH.sub.2-p-C.sub.6H.sub.4F 6-Me CH H 555.01 556 (MH) I-46
7-NHSO.sub.2-n-C.sub.3H.sub.9 --CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H
5- 87.62 588 (MH) I-47 7-N(Me)SO.sub.2Me
--CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 573.6 214-21- 8 I-48
7-NHSO.sub.2Me CH.sub.2--(4-F-3- 6-F CH H 573.6 201-217
Me--C.sub.6H.sub.3) I-49 7-NHSO.sub.2Me CH.sub.2--(4-F-3- 6-F CH H
594.01 166-174 Cl--C.sub.6H.sub.3) I-50 7-NHSO.sub.2Me
pyrid-3-ylmethyl 6-F CH H 542.57 174-186 I-51 7-NHSO.sub.2Me
--CH.sub.2-c-C.sub.6H.sub.11 6-F CH H 547.63 184-203 I-52
7-NHSO.sub.2Me isoamyl 6-F CH H 521.59 205-219 I-53
7-NHSO.sub.2-c-C.sub.3H.sub.5 CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H
585- .61 584 (M - H) I-54 7-NHSO.sub.2Me
CH.sub.2--(3,4-di-F--C.sub.6H.sub.3) 6-F CH H 577.56 - 148.2-149.4
I-55 7-NHSO.sub.2Me CH.sub.2--(4-F-3- 6-F CH H 627.57 185.8-187
CF.sub.3--C.sub.6H.sub.3) I-56 7-NHSO.sub.2CH.sub.2Ph
CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 635.67 634 (M - H) I-57
##STR00011## CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 630.6 629 (M - H)
I-58 7-NHSO.sub.2Me CH.sub.2-p-C.sub.6H.sub.4F 6-OMe CH H 571.6 570
(M - H) I-59 7-NHSO.sub.2Me CH.sub.2-p-C.sub.6H.sub.4F 6-Cl CH H
576.02 574 (M - H) I-60 7-NHSO.sub.2-i-Pr
CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 587.62 586 (M - H) I-61
7-NHSO.sub.2-n-C.sub.4H.sub.9 CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H
601- .65 600 (M - H) I-62 7-NHSO.sub.2NMe.sub.2
CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 588.61 587 (M - H) I-63
7-NHSO.sub.2NH-Boc CH.sub.2-p-C.sub.6H.sub.4F 6-F CH H 660.67 659
(M - H) I-64 7-NHSO.sub.2NH.sub.2 CH.sub.2-p-C.sub.6H.sub.4F 6-F CH
H 560.56 559 (M - H) I-65 ##STR00012## CH.sub.2-p-C.sub.6H.sub.4F
6-F CH H 614.65 613 (M - H) I-66.sup.2 7-NHSO.sub.2Me
pyridin-4-yl-methyl 6-F CH H 542.47 543 (M + H) 167-169 I-67
7-NHSO.sub.2Me CH.sub.2-p-C.sub.6H.sub.4F 7-Cl CH H 576.03 576 (M -
H) -- 574 (M - H) I-68 7-CH.sub.2OMe CH.sub.2-p-C.sub.6H.sub.4F 6-F
CH H 510.52 509 (M - H) I-69 7-NHSO.sub.2Me
CH.sub.2-p-C.sub.6H.sub.4F 6,7-di- CH H 577.56 576 (M - H) F I-70
7-NHSO.sub.2Me pyridin-2-yl-methyl 6-F CH H 542.57 172-215 I-71
7-NH.sub.2 CH.sub.2--(4-F-3- 6-Cl CH H 511.96 512 (M + H)
Me--C.sub.6H.sub.3) 510 (M - H) I-72 7-Br
CH.sub.2-p-C.sub.6H.sub.4F 7_F CH H 545.36 543 & 545 (M - H)
(I-A-7) ##STR00013## No. R.sup.1 R.sup.2 R.sup.6 Y mw ms mp I-73
7-NH.sub.2 CH.sub.2-p-C.sub.6H.sub.4F Me -- H 483.54 484 (M + H)
I-74 7-NHSO.sub.2Me CH.sub.2-p-C.sub.6H.sub.4F Me -- H 561.64 562
(M + H) I-75 7-NHSO.sub.2Me CH.sub.2-p-C.sub.6H.sub.4F H -- H
547.61 546 (M - H) I-76 7-NHSO.sub.2Me CH.sub.2-p-C.sub.6H.sub.4F
Et -- H 575.66 576 (M + H) (I-A-8) ##STR00014## No. R.sup.1 R.sup.2
Y mw ms mp I-77 7-NHSO.sub.2Me CH.sub.2-p-C.sub.6H.sub.4F H 547.61
548 (M + H) .sup.1decomposition .sup.2TFA salt
4-Hydroxy-1,5-dihydro-pyrrol-2-ones (I-A-3; TABLE 2) of the present
invention can be prepared by base-catalyzed intramolecular
cyclization of 2-(alkyl-(hetero)aryl-acetylamino)-alkanoic esters.
The cyclization has been utilized for the solid phase synthesis of
tetramic acids (J. Matthews and R. A. Rivero, J. Org. Chem. 1998
63(14):4808-4810). Amides 12 were prepared by condensation of
either 4a or 4b with an N-substituted .alpha.-amino acid ester. One
skilled in the art will appreciate that amino acids with a diverse
substitution at the .alpha.-position are very accessible and can be
used to prepare compounds within the scope of the present
invention.
##STR00015##
Acylation of 11b is carried out by standard methodology. Such
acylations are conveniently carried out with a corresponding acyl
halide or acid anhydride in a solvent such as methylene chloride,
chloroform, carbon tetrachloride, ether, THF, dioxane, benzene,
toluene, MeCN, DMF, aqueous sodium hydroxide solution or sulfolane
optionally in the presence of an inorganic or organic base at
temperatures between -20 and 200.degree. C., but preferably at
temperatures between -10 and 160.degree. C. Typical organic bases,
e.g., tertiary amines, include but are not limited to TEA,
pyridine. Typical inorganic bases include but are not limited to
K.sub.2CO.sub.3 and NaHCO.sub.3.
The acylation may however also be carried out with the free acid
optionally in the presence of an acid-activating agent or a
dehydrating agent, e.g. in the presence of isobutyl chloroformate,
thionyl chloride, trimethylchlorosilane, hydrogen chloride,
sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid,
phosphorus trichloride, phosphorus pentoxide, DCC, DCC/HOBt or
HOBt, N,N'-carbonyldiimidazole,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium
tetrafluoroborate/NMM,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium
tetrafluoroborate/DIPEA, N,N'-thionyldiimidazole or
Ph.sub.3P/CCl.sub.4, at temperatures between -20 and 200.degree.
C., but preferably at temperatures between -10 and 160.degree.
C.
The N-substituent on the pyrrolidone ring can be introduced by
alkylation or reductive alkylation. These processes afford
significant flexibility in the selection and introduction of an
N-substituent. Reductive amination is preferably carried out by
combining an amine and carbonyl compound in the presence of a
complex metal hydride such as sodium borohydride, lithium
borohydride, sodium cyanoborohydride, zinc borohydride, sodium
triacetoxyborohydride or borane/pyridine conveniently at a pH of
1-7 optionally in the presence of a dehydrating agent, such as
molecular sieve or Ti(IV)(O-i-Pr).sub.4 to facilitate formation of
the intermediate imine at ambient temperature. Alternatively,
formation of the imine in the presence of hydrogen and a
hydrogenation catalyst, e.g. in the presence of palladium/charcoal,
at a hydrogen pressure of 1 to 5 bar, preferably at temperatures
between 20.degree. C. and the boiling temperature of the solvent
used. It may also be advantageous to protect reactive groups during
the reaction using conventional protecting groups which are cleaved
again by conventional methods after the reaction. Reductive
amination procedures have been reviewed: R. M. Hutchings and M. K.
Hutchings Reduction of C.dbd.N to CHNH by Metal Hydrides in
Comprehensive Organic Synthesis col. 8, I. Fleming (Ed) Pergamon,
Oxford 1991 pp. 47-54.
Sodium tert-butoxide induced intramolecular cyclization of 12
affords the 4-hydroxy-1-(3-methyl-butyl)-1,5-dihydro-pyrrol-2-one
(13). While the cyclization is herein exemplified with sodium
tert-butoxide, a variety of strong bases including potassium
tert-butoxide, lithium diisopropyl amide (and other lithium
dialkylamides), lithium hexamethyldisilazane and sodium hydride
could be used interchangeably. The reaction is commonly carried out
in ethereal solvents such as THF, dioxane or DME. Sodium or
potassium alkoxides in alcoholic solvents can also be used in the
cyclization. The reaction can be accomplished between -70 and
60.degree. C.
TABLE-US-00002 TABLE 2 (I-A-3) ##STR00016## Cpd. No R.sup.1 R.sup.2
R.sup.4 mw ms mp II-1 H (CH.sub.2).sub.2CMe.sub.2 t-Bu 404.53 405
(MH) 85-87 II-2 H (CH.sub.2).sub.2CMe.sub.2 c-C.sub.6H.sub.11
430.57 429 (M - H) 98-100 II-3 H (CH.sub.2).sub.2CMe.sub.2 CHMe(Et)
404.53 403 (M - H) 72-80 II-4 H CH.sub.2Ph CHMe(Et) 424.52 423 (M -
H) 88-95 II-5 H --CH.sub.2-p-C.sub.6H.sub.4F CH.sub.2CHMe.sub.2
442.51 160 (d) II-6 H --CH.sub.2-p-C.sub.6H.sub.4F
-c-C.sub.6H.sub.11 468.55 467 (M - H) 180 (d) II-7.sup.1 H
--CH.sub.2-p-C.sub.6H.sub.4F -c-C.sub.6H.sub.11 468.55 >2- 50
II-8 7-NHSO.sub.2Me --CH.sub.2-p-C.sub.6H.sub.4F t-Bu 535.61 534 (M
- H) 165-172 II-9 7-NHSO.sub.2Me 4-F-3-Me-C.sub.6H.sub.3CH.sub.2--
t-Bu 549.64 548 (M - H) 173-176 II-10 7-NHSO.sub.2Me
4-F-3-MeO--C.sub.6H.sub.3CH.sub.2-- t-Bu 565.64 564 (M - H) 175-180
II-11 7-NHSO.sub.2Me 4-F-3-Cl--C.sub.6H.sub.3CH.sub.2-- t-Bu 570.06
165-1- 70 II-12 7-NO.sub.2 --CH.sub.2-p-C.sub.6H.sub.4F t-Bu 487.51
138-147 II-13 7-NH.sub.2 --CH.sub.2-p-C.sub.6H.sub.4F t-Bu 457.52
146-155 II-14 7-NHSO.sub.2NH.sub.2 --CH.sub.2-p-C.sub.6H.sub.4F
t-Bu 536.60 150-1- 56 II-15 7-NH.sub.2
--(CH.sub.2).sub.2-c-C.sub.3H.sub.5 t-Bu 417.53 105-110 II-16
7-NHSO.sub.2Me --(CH.sub.2).sub.2-c-C.sub.3H.sub.5 t-Bu 495.62
140-- 145 II-17 ##STR00017## 443.49
Pyridone compounds (15, TABLE 3) of the present invention are
prepared by condensation of 24 with a 1,3-oxazine-2,5-diones 14 in
analogy with the preparation of
4-hydroxy-1-alkyl-3-aryl-1H-quinolin-2-ones starting with an
isatoic acid anhydrides. The synthesis of oxazinediones has
been
##STR00018## described by E. M. Beccalli et al. J. Org. Chem. 1987
52(15):3426-3434; Tetrahedron Lett. 1986 27(5):627-630 and by J. H.
MacMillan and S. S. Washburn J. Het. Chem. 1975 12:1215-1220.
TABLE-US-00003 TABLE 3 (I-A-2) ##STR00019## Cpd. No. R.sup.1
R.sup.2 R.sup.3 R.sup.5 mw ms mp III-1 H (CH.sub.2).sub.2CMe.sub.2
H Me 450.56 449 (M - H) 118-121
Isoquinoline compounds (TABLE 4) of the present invention are
prepared as depicted in SCHEME 3. The key step in the preparation
is the condensation of a deprotonated ortho-substituted
methylsulfonyl aniline 34 and an
alkyl-(4-(ar)alkyl)-4-methoxyisoquinoline-3-carboxylate 33 and
subsequent intermolecular condensation of the resulting amino
ketone to afford the 4H-benzo[1,4]thiazine 1,1-dioxide ring.
Deprotonation of the sulfone is accomplished with an alkyl lithium
in an non-protic solvent. Etheral solvents such as THF, diethyl
ether, DME and dioxane are commonly used for this purpose; however,
other solvents with in which the lithiated sulfone is soluble and
which do not react with the alkyl lithium can be used
interchangeably. In addition to alkyl lithium, non-nucleophilic
dialkyl amide bases, e.g., lithium diisopropylamide and lithium
hexamethyl disilazane, sodium and potassium hydride also can be
used.
##STR00020##
The requisite
alkyl-(4-(ar)alkyl)-4-methoxyisoquinoline-3-carboxylate precursors
can be prepared from an appropriately substituted
4-hydroxy-3-carbomethoxy-1(2H)-isoquinolone (31). The isoquinolones
can be prepared by the Gabriel-Colman rearrangement of
phthalimidoacetic acids (Gabriel and Colman, Chem Ber. 1902
35:2421; L. R. Caswell and P. C. Atkinson; J. Heterocyclic Chem.
1966 3:328-332; W. Gensler, Isoquinoline in Heterocyclic Compounds,
R. C. Elderfield, ed. John Wiley & Sons, NY 1952, pp. 376-379).
Chlorination of the 1-oxo-1,2-dihydro-isoquinoline moiety is
readily accomplished with POCl.sub.3 or PCl.sub.5. Protection of
the phenol as an alkyl ether is readily accomplished by treating
the phenol with an alkylating agent in the presence of a basic
capable of deprotonating the phenol. Alkyl halides, dialkyl
sulfates and sulfonate esters of alcohols are commonly used
alkylating agents while alkali metal salts, e.g., K.sub.2CO.sub.3,
Na.sub.2CO.sub.3 or Cs.sub.2CO.sub.3, alkali metal alkoxides or
hydrides are convenient bases. Deprotection of the methyl ether was
achieved with boron tribromide in CH.sub.2Cl.sub.2 maintained at
0.degree. C. Numerous alternative protecting groups and protocols
for alkylation and dealkylation are known in the art and can be
employed to prepare compounds of the present invention. Reagents
and protocols for deprotection are described in T. W. Greene and P.
G. M. Wuts, Protective Groups in Organic Synthesis, Wiley &
Sons, New York 1999.
Introduction of the substiuent at the 1-position (SCHEME 3; step 3)
was accomplished utilizing a palladium-catalyzed coupling. The
Negishi coupling of organozinc halides or dialkylzinc with
haloarenes and aryl triflates is an effective means for attachment
of an alkyl group to an arene. The reaction is catalyzed by
palladium Pd(0) and palladium is preferably ligated to a bidentate
ligand including Pd(dppf)Cl.sub.2 and Pd(dppe)Cl.sub.2. (J. M.
Herbert Tetrahedron Lett. 2004 45:817-819). Typically the reaction
is run an inert aprotic solvent and common ethereal solvents
include dioxane, DME and THF are suitable. The reaction is commonly
run at elevated temperature.
TABLE-US-00004 TABLE 4 (I-A-5) ##STR00021## R.sup.1 R.sup.3 R.sup.2
R.sup.6 mw mp ms IV-1 H H --CH.sub.2-p-C.sub.6H.sub.4F H 432.47
267-269 IV-2 H H --CH.sub.2-p-C.sub.6H.sub.4F Me 446.5 115-120 IV-3
Cl H --CH.sub.2-p-C.sub.6H.sub.4F Me 480.94 >275 IV-4 Cl F
--CH.sub.2-p-C.sub.6H.sub.4F Me 498.94 254-256
Administration
The compounds of the present invention may be formulated in a wide
variety of oral administration dosage forms and carriers. Oral
administration can be in the form of tablets, coated tablets,
dragees, hard and soft gelatine capsules, solutions, emulsions,
syrups, or suspensions. Compounds of the present invention are
efficacious when administered by other routes of administration
including continuous (intravenous drip) topical parenteral,
intramuscular, intravenous, subcutaneous, transdermal (which may
include a penetration enhancement agent), buccal, nasal, inhalation
and suppository administration, among other routes of
administration. The preferred manner of administration is generally
oral using a convenient daily dosing regimen which can be adjusted
according to the degree of affliction and the patient's response to
the active ingredient.
A compound or compounds of the present invention, as well as their
pharmaceutically useable salts, together with one or more
conventional excipients, carriers, or diluents, may be placed into
the form of pharmaceutical compositions and unit dosages. The
pharmaceutical compositions and unit dosage forms may be comprised
of conventional ingredients in conventional proportions, with or
without additional active compounds or principles, and the unit
dosage forms may contain any suitable effective amount of the
active ingredient commensurate with the intended daily dosage range
to be employed. The pharmaceutical compositions may be employed as
solids, such as tablets or filled capsules, semisolids, powders,
sustained release formulations, or liquids such as solutions,
suspensions, emulsions, elixirs, or filled capsules for oral use;
or in the form of suppositories for rectal or vaginal
administration; or in the form of sterile injectable solutions for
parenteral use. A typical preparation will contain from about 5% to
about 95% active compound or compounds (w/w). The term
"preparation" or "dosage form" is intended to include both solid
and liquid formulations of the active compound and one skilled in
the art will appreciate that an active ingredient can exist in
different preparations depending on the target organ or tissue and
on the desired dose and pharmacokinetic parameters.
The term "excipient" as used herein refers to a compound that is
useful in preparing a pharmaceutical composition, generally safe,
non-toxic and neither biologically nor otherwise undesirable, and
includes excipients that are acceptable for veterinary use as well
as human pharmaceutical use. The term "excipient" as used herein
includes both one and more than one such excipient.
A "pharmaceutically acceptable salt" form of an active ingredient
may also initially confer a desirable pharmacokinetic property on
the active ingredient which were absent in the non-salt form, and
may even positively affect the pharmacodynamics of the active
ingredient with respect to its therapeutic activity in the body.
The phrase "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Such salts
include: (1) acid addition salts, formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid,
glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,
muconic acid, and the like; or (2) salts formed when an acidic
proton present in the parent compound either is replaced by a metal
ion, e.g., an alkali metal ion, an alkaline earth ion, or an
aluminum ion; or coordinates with an organic base such as
ethanolamine, diethanolamine, triethanolamine, tromethamine,
N-methylglucamine, and the like. It should be understood that all
references to pharmaceutically acceptable salts include solvent
addition forms (solvates) or crystal forms (polymorphs) as defined
herein, of the same acid addition salt.
Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories, and dispersible granules. A solid carrier
may be one or more substances which may also act as diluents,
flavoring agents, solubilizers, lubricants, suspending agents,
binders, preservatives, tablet disintegrating agents, or an
encapsulating material. In powders, the carrier generally is a
finely divided solid which is a mixture with the finely divided
active component. In tablets, the active component generally is
mixed with the carrier having the necessary binding capacity in
suitable proportions and compacted in the shape and size desired.
Suitable carriers include but are not limited to magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. Solid form preparations may contain, in addition to the
active component, colorants, flavors, stabilizers, buffers,
artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like.
Liquid formulations also are suitable for oral administration
include liquid formulation including emulsions, syrups, elixirs,
aqueous solutions and aqueous suspensions. These include solid form
preparations which are intended to be converted to liquid form
preparations shortly before use. Emulsions may be prepared in
solutions, for example, in aqueous propylene glycol solutions or
may contain emulsifying agents such as lecithin, sorbitan
monooleate, or acacia. Aqueous solutions can be prepared by
dissolving the active component in water and adding suitable
colorants, flavors, stabilizing, and thickening agents. Aqueous
suspensions can be prepared by dispersing the finely divided active
component in water with viscous material, such as natural or
synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, and other well known suspending agents.
The compounds of the present invention may be formulated for
parenteral administration (e.g., by injection, for example bolus
injection or continuous infusion) and may be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions
may take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, for example solutions in aqueous polyethylene
glycol. Examples of oily or nonaqueous carriers, diluents, solvents
or vehicles include propylene glycol, polyethylene glycol,
vegetable oils (e.g., olive oil), and injectable organic esters
(e.g., ethyl oleate), and may contain formulatory agents such as
preserving, wetting, emulsifying or suspending, stabilizing and/or
dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilisation from solution for constitution before use with a
suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for
topical administration to the epidermis as ointments, creams or
lotions, or as a transdermal patch. Ointments and creams may, for
example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
containing one or more emulsifying agents, stabilizing agents,
dispersing agents, suspending agents, thickening agents, or
coloring agents. Formulations suitable for topical administration
in the mouth include lozenges comprising active agents in a
flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatin
and glycerin or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for
administration as suppositories. A low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter is first melted
and the active component is dispersed homogeneously, for example,
by stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for
vaginal administration. Pessaries, tampons, creams, gels, pastes,
foams or sprays containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal
administration. The solutions or suspensions are applied directly
to the nasal cavity by conventional means, for example, with a
dropper, pipette or spray. The formulations may be provided in a
single or multidose form. In the latter case of a dropper or
pipette, this may be achieved by the patient administering an
appropriate, predetermined volume of the solution or suspension. In
the case of a spray, this may be achieved for example by means of a
metering atomizing spray pump.
The compounds of the present invention may be formulated for
aerosol administration, particularly to the respiratory tract and
including intranasal administration. The compound will generally
have a small particle size for example of the order of five (5)
microns or less. Such a particle size may be obtained by means
known in the art, for example by micronization. The active
ingredient is provided in a pressurized pack with a suitable
propellant such as a chlorofluorocarbon (CFC), for example,
dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
The aerosol may conveniently also contain a surfactant such as
lecithin. The dose of drug may be controlled by a metered valve.
Alternatively the active ingredients may be provided in a form of a
dry powder, for example a powder mix of the compound in a suitable
powder base such as lactose, starch, starch derivatives such as
hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The
powder carrier will form a gel in the nasal cavity. The powder
composition may be presented in unit dose form for example in
capsules or cartridges of e.g., gelatin or blister packs from which
the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings
adapted for sustained or controlled release administration of the
active ingredient. For example, the compounds of the present
invention can be formulated in transdermal or subcutaneous drug
delivery devices. These delivery systems are advantageous when
sustained release of the compound is necessary and when patient
compliance with a treatment regimen is crucial. Compounds in
transdermal delivery systems are frequently attached to a
skin-adhesive solid support. The compound of interest can also be
combined with a penetration enhancer, e.g., Azone
(1-dodecylaza-cycloheptan-2-one). Sustained release delivery
systems are inserted subcutaneously into to the subdermal layer by
surgery or injection. The subdermal implants encapsulate the
compound in a lipid soluble membrane, e.g., silicone rubber, or a
biodegradable polymer, e.g., polylactic acid.
Suitable formulations along with pharmaceutical carriers, diluents
and expcipients are described in Remington: The Science and
Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing
Company, 19th edition, Easton, Pa. A skilled formulation scientist
may modify the formulations within the teachings of the
specification to provide numerous formulations for a particular
route of administration without rendering the compositions of the
present invention unstable or compromising their therapeutic
activity.
The modification of the present compounds to render them more
soluble in water or other vehicle, for example, may be easily
accomplished by minor modifications (salt formulation,
esterification, etc.), which are well within the ordinary skill in
the art. It is also well within the ordinary skill of the art to
modify the route of administration and dosage regimen of a
particular compound in order to manage the pharmacokinetics of the
present compounds for maximum beneficial effect in patients.
The term "therapeutically effective amount" as used herein means an
amount required to reduce symptoms of the disease in an individual.
The dose will be adjusted to the individual requirements in each
particular case. That dosage can vary within wide limits depending
upon numerous factors such as the severity of the disease to be
treated, the age and general health condition of the patient, other
medicaments with which the patient is being treated, the route and
form of administration and the preferences and experience of the
medical practitioner involved. For oral administration, a daily
dosage of between about 0.01 and about 100 mg/kg body weight per
day should be appropriate in monotherapy and/or in combination
therapy. A preferred daily dosage is between about 0.1 and about
500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body
weight and most preferred 1.0 and about 10 mg/kg body weight per
day. Thus, for administration to a 70 kg person, the dosage range
would be about 7 mg to 0.7 g per day. The daily dosage can be
administered as a single dosage or in divided dosages, typically
between 1 and 5 dosages per day. Generally, treatment is initiated
with smaller dosages which are less than the optimum dose of the
compound. Thereafter, the dosage is increased by small increments
until the optimum effect for the individual patient is reached. One
of ordinary skill in treating diseases described herein will be
able, without undue experimentation and in reliance on personal
knowledge, experience and the disclosures of this application, to
ascertain a therapeutically effective amount of the compounds of
the present invention for a given disease and patient.
In embodiments of the invention, the active compound or a salt can
be administered in combination with another antiviral agent such as
ribavirin, a nucleoside HCV polymerase inhibitor, another HCV
non-nucleoside polymerase inhibitor or HCV protease inhibitor. When
the active compound or its derivative or salt are administered in
combination with another antiviral agent the activity may be
increased over the parent compound. When the treatment is
combination therapy, such administration may be concurrent or
sequential with respect to that of the nucleoside derivatives.
"Concurrent administration" as used herein thus includes
administration of the agents at the same time or at different
times. Administration of two or more agents at the same time can be
achieved by a single formulation containing two or more active
ingredients or by substantially simultaneous administration of two
or more dosage forms with a single active agent.
It will be understood that references herein to treatment extend to
prophylaxis as well as to the treatment of existing conditions.
Furthermore, the term "treatment" of a HCV infection, as used
herein, also includes treatment or prophylaxis of a disease or a
condition associated with or mediated by HCV infection, or the
clinical symptoms thereof.
The pharmaceutical preparations are preferably in unit dosage
forms. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, cachet, or lozenge itself, or it can
be the appropriate number of any of these in packaged form.
Examples of the preparation and testing of representative compounds
encompassed by the present invention and within the scope of the
invention are provided in the following examples. These examples
and preparations which follow are provided to enable those skilled
in the art to more clearly understand and to practice the present
invention. They should not be considered as limiting the scope of
the invention, but merely as being illustrative and representative
thereof.
EXAMPLE 1
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-4-hydroxy--
1-(3-methyl-butyl)-1H-quinolin-2-one (I-1, SCHEME 1)
step 1--To a solution of 2-aminothiophenol (4.96 g, 39.6 mmol) in
MeOH (200 mL) was added the ethyl 4-chloroacetoacetate (6.2 g, 38
mmol). After stirring at room temperature for 2 h the MeOH was
removed under reduced pressure. The residue was dissolved in
Et.sub.2O and washed with HCl (1N), saturated NaHCO.sub.3, and
brine. The organic phase was dried over MgSO.sub.4, filtered and
the solvent was removed under reduced pressure. The product was
obtained from a minimum of EtOH to afford 5.0 g (54%) of 8: LCMS RT
3.7 min, M+H.
step 2--To a solution of 8 (1.0 g, 4.3 mmol) in THF (50 mL) was
added the di-tert-butyl dicarbonate (1.86 g, 8.5 mmol) and DMAP
(1.0 g, 8.5 mmol). After stirring at rt for 1 h, the solvent was
removed under reduced pressure. The residue was dissolved in DCM
and washed with 1N HCl. The organic phase was concentrated and the
product was purified by column chromatography on SiO.sub.2 eluting
with EtOAc/hexanes to afford 1.4 g (985) of 9: LCMS RT 3.7 min,
M+H.
step 3--The BOC protected thiazine 9 (1.4 g, 4.2 mmol) was
dissolved in DCM (50 mL) and MCPBA (4.8 g, 21 mmol) was added. This
mixture was stirred vigorously for 1 h at rt. An aqueous solution
of sodium thiosulfate (1 eq) was added and stirring continued for
15 minutes. The organics were separated and washed with NaOH (1N),
HCl (1N), saturated NaHCO.sub.3, and brine. The organics were dried
over MgSO.sub.4, filtered and the solvent was removed under reduced
pressure to afford 1.3 g of 10: LCMS RT 3.27 min, M+H.sub.2O.
step 4--A solution of the BOC thiazine-1,1-dioxide 10 (1 g, 2.7
mmol) and 50% TFA/DCM was stirred for 18 h and the TFA was removed
under reduced pressure. The residue was dissolved in ethyl acetate
and washed sequentially with saturated NaHCO.sub.3 and brine. The
organics were dried over MgSO.sub.4, filtered and the solvent was
removed under reduced pressure to afford 0.7 g (97%) of 4: LCMS RT
2.07 min, M+H.
step 5--The thiazine 4 (0.20 g, 0.75 mmol) and 1-isoamyl isatoic
anhydride (5, 0.17 g, 0.75 mmol) were dissolved in EtOAc (2 ml) and
THF (2 mL). To this mixture was added DBU (0.23 g, 1.5 mmol). The
reaction mixture was heated at reflux for 30 minutes. After cooling
to rt, acetic acid (1 mL), 1N HCl (5 mL) and water were added
sequentially and the product was extracted into EtOAc. The organics
were washed with saturated NaHCO.sub.3 and brine. The organic phase
was dried over MgSO.sub.4, filtered and the solvent was removed
under reduced pressure. The product was purified by column
chromatography on SiO.sub.2 eluting with EtOAc/hexanes to afford
0.08 g (26%) of I-1: LCMS RT 3.86 min, M+H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 1-(2-cyclopropylethyl)-6-fluoro-isoatoic anhydride in the
final step there was obtained 0.032 g (9%) of
1-(2-cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-fluoro-4-hydroxy-1H-quinolin-2-one (I-2): LCMS RT
3.69 min, M+H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 1-isoamyl-6-chloro-isoatoic anhydride in the final step there
was obtained 0.104 g (31%) of
1-isoamyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-
-6-chloro-4-hydroxy-1H-quinolin-2-one (I-3): LCMS RT 4.13 min,
M+H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 1-(2-cyclopropylethyl)-6-methyl-isoatoic anhydride in the
final step there was obtained 0.040 g (36%) of
1-(2-cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-methyl-4-hydroxy-1H-quinolin-2-one (I-4): LCMS RT
2.90 min, M-H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 1-(2-cyclopropylethyl)-6-methoxy-isoatoic anhydride in the
final step there was obtained 0.055 g (22%) of
1-(2-cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-methoxy-4-hydroxy-1H-quinolin-2-one (I-5): LCMS RT
3.61 min, M+H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 1-(2-cyclopropylethyl)-6-chloro-isoatoic anhydride in the
final step there was obtained 0.028 g (6%) of
1-(2-cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-chloro-4-hydroxy-1H-quinolin-2-one (I-6): LCMS RT
2.67 min, M-H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 1-(2-fluorobenzyl)-6-isoatoic anhydride in the final step
there was obtained 0.070 g (17%) of
3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(2-fluo-
robenzyl)-4-hydroxy-1H-quinolin-2-one (I-8): LCMS RT 2.49 min,
M+H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 1-(4-fluorobenzyl)-6-isoatoic anhydride in the final step
there was obtained 0.018 g (7%) of
3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
robenzyl)-4-hydroxy-1H-quinolin-2-one (I-9): LCMS RT 2.45 min, M-H.
The sodium salt I-9a was prepared by suspending I-9 (22 mg, 0.05
mmol) in MeCN (1 mL) and adding 0.1N NaOH (490 .mu.L). The
resulting mixture was stirred for 5 minutes to give a homogeneous
solution. The mixture was lyophilized to afford 23 mg (100%) of
I-9a as a light yellow solid: LCMS RT 2.37 min, M-H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 8-aza-1-(2-cyclopropylethyl) isatoic anhydride in the final
step there was obtained 0.083 g (31%) of
1-(2-cyclopropyl-ethyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-4-hydroxy-1H-[1,8]naphthyridin-2-one (I-10): LCMS RT
3.59 min, M+H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 8-aza-1-isoamyl-isatoic anhydride in the final step there was
obtained 0.080 g (30%) of
1-isoamyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-
-4-hydroxy-1H-[1,8]naphthyridin-2-one (I-11): LCMS RT 2.39 min,
M-H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 8-aza-6-fluoro-1-isoamyl-isatoic anhydride in the final step
there was obtained 0.150 g (49%) of
3-(1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-3-yl)-6-fluoro-4-hyd-
roxy-1-(3-methyl-butyl)-1H-[1,8]naphthyridin-2-one (I-12): LCMS RT
3.94 min, M+H.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 6-fluoro-1-(3,4-difluorobenzyl-isatoic anhydride in the final
step there was obtained 0.120 g (51%) of
1-(3,4-difluoro-benzyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4-
]thiazin-3-yl)-6-fluoro-4-hydroxy-1H-quinolin-2-one (I-25): ms
[M-H]=483.3. The sodium salt I-25a was prepared as described above
for I-9a.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 6-fluoro-1-(4-fluoro-3-methyl-benzyl-isatoic anhydride in the
final step there was obtained 0.065 g (27.3%) of
3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-1H-quinolin-2-one (I-26): ms
[M-H]=479.3. The sodium salt I-26a was prepared as described above
for I-9a.
Using the same procedure but replacing 1-isoamyl-isatoic anhydride
with 6-fluoro-1-(3-cyano-benzyl-isatoic anhydride in the final step
there was obtained 0.140 g (58.5%) of
3-[3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluo-
ro-4-hydroxy-2-oxo-2H-quinolin-1-ylmethyl]-benzonitrile (I-27): ms
[M-H]=472.3. The sodium salt I-27a was prepared as described above
for I-9a.
EXAMPLE 2
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro-1-
-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one (I-13)
To a solution of thiazine acetic acid ester 4 (0.20 g, 0.69 mmol)
in THF was added NaH (0.11 g, 60% in oil, 2.8 mmol). After 10 min,
1-(4-fluorobenzyl)-6-fluoro-isatoic anhydride (22) was added. The
reaction mixture was heated at reflux for 30 min and then the
mixture was cooled to rt. HOAc (1 mL) was added and the mixture was
heated again at reflux for 30 min. The solvent was removed under
reduced pressure and 1N HCl (10 mL) was added to the residue. The
mixture was extracted with Et.sub.2O. The combined organic phase
was washed with brine and dried (MgSO.sub.4), filtered and the
solvent was removed under reduced pressure. The residue was
dissolved in DCM and then concentrated under reduced pressure. This
process was repeated. The resulting solid was dried under vacuum.
The product was triturated with Et.sub.2O, which required
sonication, and the resulting precipitate collected by filtration,
and dried in vacuo to afford 200 mg (62%) of I-13: LCMS RT 2.46
min, M-H.
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6-fluoro--
1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one, sodium salt
(I-13a) was prepared using a procedure similar to that described
for I-8a. The mixture was lyophilized to afford 31 mg (100%) of
I-13a as a light yellow solid: LCMS RT 2.50 min, M-H.
Using the procedure of Example 2 but replacing 1-isoamyl-isatoic
anhydride with 1-(4-fluorobenzyl)-6-methyl-isatoic anhydride there
was obtained 0.186 g (57%) of
3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluo-
ro-benzyl)-4-hydroxy-6-methyl-1H-quinolin-2-one (I-14): LCMS RT
2.48 min, M-H. The sodium salt I-14a was prepared as described for
I-9a (supra) and afforded 0.031 g (100%): LCMS RT 2.48 min,
M-H.
Using the procedure of Example 2 but replacing ethyl benzothiazine
acetate with ethyl 6-chlorobenzthiazine acetate there was obtained
0.050 g (33%) of
3-(6-chloro-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)--
4-hydroxy-1-(3-methyl-butyl)-1H-quinolin-2-one (I-7): LCMS RT 2.7
min, M-H.
EXAMPLE 3
3-(6-Fluoro-4-hydroxy-1-isobutyl-2-oxo-1,2-dihydro-quinolin-3-yl)-1,1-diox-
o-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazine-6-carbonitrile
(I-16)
A tube was charged with I-7 (0.400 g, 0.9 mmol), Zn(CN).sub.2 (63
mg, 0.54 mmol), DPPF (100 mg, 0.18 mmol), zinc dust (35 mg, 0.54
mmol, and Pd.sub.2(dba).sub.3 (82 mg, 0.89 mmol). The tube was
purged with N.sub.2, sealed and heated to 120.degree. C. for 3.5 h.
After cooling, the mixture was poured into 10% aqueous NH.sub.4OH.
The solution was washed with ether. The product was extracted into
EtOAc. The organic phase was washed with brine and dried over
MgSO.sub.4. The product was purified by column chromatography on
SiO.sub.2 eluting with EtOAc/MeOH to afford 0.115 g (29%) of I-16:
LCMS RT 2.65 min, M-H.
EXAMPLE 4
3-(6-Aminomethyl-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3--
yl)-6-fluoro-4-hydroxy-1-isobutyl-1H-quinolin-2-one (I-17)
The nitrile I-16 (110 mg, 0.25 mmol) from Example 3 was dissolved
in MeOH (5 mL). CoCl.sub.2 (120 mg, 0.5 mmol) was added. The
resulting suspension was stirred at rt until the CoCl.sub.2
dissolved. The mixture was cooled to 0 C. and NaBH.sub.4 (95 mg,
2.5 mmol) was added. Upon addition, the mixture turned black and
gas evolution was observed. The reaction mixture was stirred at RT
for 30 min and then cooled to 0.degree. C. The pH was adjusted to 2
by addition of 1N HCl. The resulting solution was stirred at
0.degree. C. for 30 min and then neutralized with saturated
NaHCO.sub.3. The solution was washed with ether and then made basic
with a Na.sub.2CO.sub.3 solution and the resulting mixture was
extracted into EtOAc which was dried (MgSO.sub.4) filtered and
evaporated to afford 0.11 g (10%) of I-17: LCMS RT 2.62 min,
M+H.
EXAMPLE 5
(S)-5-tert-Butyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-
-3-yl)-4-hydroxy-1-(3-methyl-butyl)-1,5-dihydro-pyrrol-2-one (II-1,
SCHEME 2)
step 1--The ester 4a (250 mg, 0.93 mmol) was dissolved in a
solution of 50% ethanol containing 50% 1N NaOH (3 mL total volume)
and heated to 80.degree. C. After 15 min the reaction mixture was
cooled to RT and washed with Et.sub.2O. The aqueous solution was
acidified with 1N HCl and extracted with ether. The combined
Et.sub.2O extracts were washed with brine and dried (MgSO.sub.4)
and the solvents were removed under reduced pressure to afford
0.120 g (54%) of 4b: LCMS RT 1.25 min.
step 2--To a solution of O(t-Bu)-t-butylglycine HCl (11a, 2 g, 8.9
mmol) in MeOH containing 10% acetic acid was added 3-methyl
butyraldehyde (1.5 g, 18 mmol) and NaCNBH.sub.3 (1.1 g, 18 mmol).
This mixture stirred at room temperature for 1 h. The reaction
mixture was poured into 1N NaOH. The product was extracted into
EtOAc. The organic layer was washed with 1N HCl and brine, dried
(MgSO.sub.4) and volatile solvents removed under reduced pressure
to afford 2.0 g (87%) of 11b: LCMS RT 2.49 min, M+H.
step 3--To a solution of 4b (120 mg, 0.5 mmol) in DCM (5 mL) and
DMF (1 mL) was added 11b (130 mg, 0.5 mmol). To this mixture was
added DCC (63 mg, 0.5 mmol). The reaction stirred at RT for 30 min,
diluted with DCM and washed with 1N NaOH and brine. The combined
organic phases were dried (MgSO.sub.4) and the volatile solvents
were removed under reduced pressure. The crude product was purified
by column chromatography on SiO.sub.2 eluting with EtOAc/hexanes to
afford 0.100 g (41%) of 12: LCMS RT 3.81, 4.03 min, M+H.
step 4--A mixture of 12 (100 mg, 0.21 mmol) and t-BuONa (50 mg,
0.52 mmol) in IPA (5 mL) was stirred at RT for 2 h. The reaction
was quenched by the addition of 1 N HCl (10 mL). The product was
extracted into DCM and the organic layer was washed with brine and
dried (MgSO.sub.4). The solvent was removed under reduced pressure
and the product was purified using column chromatography on
SiO.sub.2 eluting with EtOAc/hexane to afford 0.045 g (54%) of 13
(II-1): LCMS RT 3.82 min, M+H.
Using the procedure of Example 6 but replacing
O(t-Bu)-t-butylglycine HCl in step 2 with O(t-Bu) cyclohexyl
glycine there was obtained 0.085 g (32%) of
(S)-5-Cyclohexyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1-
,4]thiazin-3-yl)-4-hydroxy-1-isobutyl-1,5-dihydro-pyrrol-2-one
(II-2): LCMS RT 3.08 min, M-H.
Using the procedure of Example 6 but replacing
O(t-Bu)-t-butylglycine HCl in step 2 with O(t-Bu) isoleucine there
was obtained 0.135 g (53%) of
(S)-5-((S)-sec-Butyl)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]t-
hiazin-3-yl)-4-hydroxy-1-isobutyl-1,5-dihydro-pyrrol-2-one (II-3):
LCMS RT 2.89 min, M-H.
Using the procedure of Example 6 but replacing
O(t-Bu)-t-butylglycine HCl in step 2 with O(t-Bu) isoleucine and
3-methyl-butyraldehyde with benzaldehyde there was obtained 0.354 g
(56%) of
1-benzyl-5-sec-butyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]th-
iazin-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one (II-4): LCMS RT 2.60
min, M-H.
Using the procedure of Example 6 but replacing
O(t-Bu)-t-butylglycine HCl in step 2 with O(t-Bu)leucine and
3-methyl-butyraldehyde with 4-fluoro-benzaldehyde
(S)-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1-(4--
fluoro-benzyl)-4-hydroxy-5-isobutyl-1,5-dihydro-pyrrol-2-one
(II-5).
Using the procedure of Example 6 but replacing
O(t-Bu)-t-butylglycine HCl in step 2 with O(t-Bu)cyclohexylglycine
and 3-methyl-butyraldehyde with 4-fluoro-benzaldehyde
(S)-5-cyclohexyl-3-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one
(II-6).
EXAMPLE 6
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-hydroxy-1,1-dioxo-1,4-dihydro--
1.lamda.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one (I-18) and
2-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.sup.6-benzo[1,4]thiazin-7-yloxy}-acetamide
(I-20)
##STR00022##
step 1--To a solution of 4-benzyloxyaniline (18, 10.0 g, 50 mmol)
in HOAc (50 mL) was added sulfur monochloride (16.9 g, 125 mmol).
After stirring at RT for 1 h the mixture was heated to 75.degree.
C. for 2 h. The mixture was cooled to RT and toluene (150 mL) was
added. The resulting red solid was collected, washed with toluene
and dried under reduced pressure to afford 12 g (81%) of 19: LCMS
RT 3.33 min.
step 2--To a suspension of 19 (9.0 g, 30 mmol) in water (50 mL) was
added Na.sub.2S.sub.2O.sub.4 (8.1 g, 40 mmol). The mixture adjusted
to pH 12 using 1N NaOH. This mixture was stirred at 50.degree. C.
for 2 h. Dioxane (50 mL) and chloroacetoacetate (10 g, 61 mmol)
were added sequentially and the temperature was maintained at
50.degree. C. for 1 h. The mixture was cooled to RT and the dioxane
was removed under in vacuo. The aqueous phase was extracted into
EtOAc and the combined aqueous phase was washed with brine and
dried over MgSO.sub.4. The product was purified by column
chromatography on SiO.sub.2 eluting with EtOAc/hexanes to afford
1.7 g (16%) of 20a: LCMS RT 4.44 min, M+H.
step 3--20a was converted to 20b as described in step 2 of Example
1. The product was used in the next step without further
purification.
step 4--20b was converted to 21a as described in step 3 of Example
1. The product was used in the next step without further
purification.
step 5--21a was converted to 21b (0.420 g, 43% for the previous
three steps, LCMS RT 2.09 min, M+H) as described in step 4 of
Example 1. The product was used in the next step without further
purification.
step 6--The condensation of thiazine acetic acid ester 21b (0.20 g,
0.69 mmol) and 1-(4-fluorobenzyl)-6-fluoro-isatoic anhydride (22)
was carried out as described in Example 2 except thiazine 4 was
replaced by 21b to afford 0.310 g (68%) of 23 (I-19): LCMS RT 2.56
min, M-H.
step 7--To a solution of 23 (220 mg, 0.38 mmol) in DCM (10 mL) at
0.degree. C. was added N,N-dimethylaniline (280 mg, 2.3 mmol) and
AlCl.sub.3 (410 mg, 3.1 mmol). The reaction stirred at 0.degree. C.
for 30 min. The mixture was poured into 1N NaOH (50 mL). The
aqueous layer was washed with EtOAc. The aqueous layer was
acidified with 1N HCl and the product was extracted into EtOAc. The
combined organic phase was washed with brine, dried (MgSO.sub.4)
and the solvent was removed in vacuo to afford 0.159 g (81%) of 24a
(I-18): LCMS RT 2.51 min, M-H).
step 8--To a solution of 24a (0.054 g, 0.112 mmol) in acetone (10
mL) was added 2-bromoacetamide (0.046 g, 0.336 mmol) and
K.sub.2CO.sub.3 (0.309 g, 3.2 mmol). The reaction was heated at
reflux for 2 h. The mixture was poured into water (50 mL). The
product was extracted with EtOAc. The combined extracts were washed
with 1N HCl and brine, dried (MgSO.sub.4) and the solvent was
removed in vacuo to afford 0.035 g (58%) of 24b (I-20): LCMS RT
2.37 min, M-H.
Using the procedure in step 8 but replacing 2-bromoacetamide with
N-methyl-2-chloroacetamide there was obtained 0.070 g (30.5%) of
2-{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-N-met-
hyl-acetamide (I-42): ms [M-H]=552.2.
Using the procedure in step 8 but replacing 2-bromoacetamide with
N,N-dimethyl-2-bromoacetamide there was obtained 0.160 g (90.7%) of
2-{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-N,N-d-
i-methyl-acetamide (I-34): ms [M-H]=566.2.
EXAMPLE 7
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3--
yl]-1,1-dioxo-1,4-dihydro-1.sup.6-benzo[1,4]thiazin-7-yl}-methanesulfonami-
de (I-24)
##STR00023##
step 1--To a solution of 6-nitro-benzothiazole (25, 2.0 g, 11 mmol)
and EtOH (20 mL) was added hydrazine monohydrate (5.0 mL, 161
mmol). After stirring at RT for 3 h the EtOH was removed under
reduced pressure. The resulting red solid was dissolved in EtOAc
and washed with a 0.1 M HCl solution. The organic phase was washed
with brine and dried over MgSO.sub.4. The solid was triturated with
Et.sub.2O and dried under reduced pressure to afford 1.8 g (94%) of
26: .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 8.35 (s, 1H),
.delta..00 (d, 1H), 6.7 (d, 1H), 4.9 (broad, 2H), 3.0 (s, 1H).
step 2--To a solution of 26 (0.50 g, 2.9 mmol) in THF (30 mL) was
added TEA (0.82 mL, 5.9 mmol). Ethyl chloroacetoacetate (7, 0.52 g,
3.2 mmol) was added and the mixture stirred at RT for 12 h. The
solvent was removed under reduced pressure and the residue was
dissolved in EtOAc. The mixture was heated at 80.degree. C. for 2
h. The mixture was cooled to RT, washed with brine and dried
(MgSO.sub.4). The product was triturated with Et.sub.2O and dried
under reduced pressure to afford 0.61 g (70%) of 27a: LCMS RT 3.48
min, M+H.
step 3--To a solution of 27a (2.00 g, 7.1 mmol) in EtOH (25 mL) was
added tin (II) chloride (6.8 g, 36 mmol) and 1N HCl (1 mL). The
mixture was heated at 100.degree. C. for 3 h. The mixture was
cooled to RT and the EtOH was removed under reduced pressure. The
residue was dissolved in EtOAc and 6N NaOH (30 mL) was added. The
mixture was filtered and the solid was washed with copious amounts
of EtOAc. The filtrate was washed with brine and dried over
Na.sub.2SO.sub.4. The product was purified by column chromatography
on SiO.sub.2 eluting with EtOAc/hexanes to afford 1.7 g (80%) of
27b: LCMS RT 2.84 min, M+H.
step 4--A solution of 27b (0.50 g, 1.9 mmol) in DCM (20 mL) and TEA
(1 mL, 6.2 mmol) was cooled to 0.degree. C. Methanesulfonyl
chloride (0.22 g, 1.9 mmol) was added dropwise over 30 min and the
resulting mixture was stirred at RT for an additional 30 min. The
solvent was removed under reduced pressure and the residue was
dissolved in EtOAc. The organic phase was washed with brine, dried
(Na.sub.2SO.sub.4) and the solvent was removed in vacuo. The
product was purified by column chromatography on SiO.sub.2 eluting
with EtOAc/hexanes to afford 0.591 g (90%) 27c: LCMS RT 2.87 min,
M+H.
step 5-step 7--Protection of the nitrogen atom (step 5), oxidation
of the sulfide (step 6) and deprotection of the nitrogen (step 7)
to afford 29b were carried out as described in example 1, steps 2-4
without purification of the intermediate products to afford 0.420 g
(78% overall) of 29b: LCMS RT 1.81 min, M-H.
step 8--The condensation of thiazine acetic acid ester 29b (0.20 g,
0.69 mmol) and 1-(4-fluorobenzyl)-6-fluoro-isatoic anhydride 22 was
carried out as described in Example 2 except thiazine 4 was
replaced by 29b to afford 0.090 g (29%) of 30 (I-24): LCMS RT 2.55
min, M-H.
Compounds I-69
(6,7-difluoro-1-(4-fluoro-benzyl)-1H-benzo[d][1,3]oxazine-2,4-dione),
I-44 (1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione), I-45
(6-fluoro-1-(4-fluoro-benzyl)-1H-benzo[d][1,3]oxazine-2,4-dione),
I-48
(6-fluoro-1-(4-fluoro-3-methyl-benzyl)-1H-benzo[d][1,3]oxazine-2,4-dione,
I-49
(1-(3-chloro-4-fluoro-benzyl)-6-fluoro-1H-benzo[d][1,3]oxazine-2,4-d-
ione, I-50
(6-fluoro-1-pyridin-3-ylmethyl-1H-benzo[d][1,3]oxazine-2,4-dion-
e), I-51
(1-cyclohexylmethyl-6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione),
I-52
(6-fluoro-1-(3-methyl-butyl)-1H-benzo[d][1,3]oxazine-2,4-dione,
I-54
(1-(3,4-difluoro-benzyl)-6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione,
I-55
(6-fluoro-1-(4-fluoro-3-trifluoromethyl-benzyl)-1H-benzo[d][1,3]oxazine-2-
,4-dione, I-58
(1-(4-fluoro-benzyl)-6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione,
I-59
(6-chloro-1-(4-fluoro-benzyl)-1H-benzo[d][1,3]oxazine-2,4-dione),
I-66
(6-fluoro-1-pyridin-4-ylmethyl-1H-benzo[d][1,3]oxazine-2,4-dione)
and I-67
(7-chloro-1-(4-fluoro-benzyl)-1H-benzo[d][1,3]oxazine-2,4-dione)were
prepared as described in Example 7 except in step 8,
1-(4-fluorobenzyl)-6-fluoroisatoic anhydride 22 was replaced by the
appropriate 1-substituted 1H-benzo[d][1,3]oxazine-2,4-dione
indicated in parentheses. Methods for the preparation of
1-substituted 1H-benzo[d][1,3]oxazine-2,4-dione (isatoic
anhydrides) are described in example 24.
EXAMPLE 8
3-(1,1-Dioxo-1,4-dihydro-1-.sup.6-benzo[1,4]thiazin-3-yl)-1-(4-fluoro-benz-
yl)-isoquinolin-4-ol (IV-1; see SCHEME 3,
R.sup.2=CH.sub.2-p-C.sub.6H.sub.4F)
step 1--Phosphorous oxychloride (40 mL) was added to a flask
containing 4-hydroxy-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic
acid methyl ester (31, 5.00 g, 22.8 mmol). After stirring at
70.degree. C. for 3 h, the POCl.sub.3 was removed under reduced
pressure, and water was added to the residue. The resulting solid
was collected by filtration, and the solid was further washed with
water and hexanes then dissolved in dichloromethane. The organic
phase was dried (MgSO.sub.4), filtered and the solvent was removed
in vacuo to afford 5.10 g, (94% theory) of 32a: LCMS RT 3.6 min,
M+H.
step 2--To a suspension of the phenol 32a (1.20 g, 5.05 mmol) in
DMF (15 mL) was added Cs.sub.2CO.sub.3 (1.97 g, 6.06 mmol) followed
by methyl iodide (1.57 mL, 25.5 mmol). After stirring at RT for 20
h, the reaction mixture was diluted with EtOAc and washed with
water (2.times.) and brine (2.times.). The organic extracts were
dried (MgSO.sub.4), filtered and the solvent was removed in vacuo
to afford 1.25 g (98% theory) of 32b LCMS RT 3.0 min, M+H.
step 3--The methyl ether 32b (0.500 g, 1.99 mmol) was dissolved in
THF (5 mL) and Pd(PPh.sub.3).sub.4 (0.230 g, 0.200 mmol) and
4-fluorobenzylzinc bromide (4.8 mL, 0.5M in THF, 2.38 mmol) were
added sequentially. This mixture was stirred vigorously for 18 h at
60.degree. C. and quenched with an aqueous solution of NH.sub.4Cl.
The product was twice extracted into EtOAc and the combined organic
layers were washed with brine, dried (MgSO.sub.4), filtered and the
solvent was removed in vacuo. The product was purified by column
chromatography on SiO.sub.2 eluting with EtOAc/hexanes to afford
0.400 g, (62% theory) of 33: LCMS RT 3.7 min, M+H.
step 4--To a solution of 2-(methylsulfonyl)benzenamine
hydrochloride (34, 182 mg, 1.66 mmol) in THF (2 mL) cooled to
-78.degree. C. was added n-BuLi (1.8 mL, 2.9 mmol; 1.6M solution in
hexanes). The yellow reaction mixture was stirred at -78.degree. C.
for 1 h, and a solution of the ester 33 (190 mg, 0.58 mmol) in THF
(1.5 mL) was added. The reaction mixture was allowed to slowly warm
to RT overnight, and the dark reaction mixture was diluted with
EtOAc. The organic layer was washed sequentially with 10% HCl,
water, and brine. The combined organic layers were dried
(MgSO.sub.4), filtered and the solvent removed in vacuo. The crude
mixture containing 35a was used directly in the next step.
step 5--To a solution of the crude product from step 4 in DCM (1
mL) and cooled to 0.degree. C. was added a 1.0M BBr.sub.3 solution
in DCM (6.0 mL, 6.0 mmol). The reaction mixture was stirred at RT
for 18 h then concentrated in vacuo. Water was added to the
residue, and the resulting solid was collected by filtration and
washed with water. The product was purified by chromatography on
SiO.sub.2 eluting with EtOAc/hexanes to afford 4 mg (20% theory) of
35b (IV-1): LCMS RT 4.0 min, M+H.
1-(4-Fluoro-benzyl)-3-(4-methyl-1,1-dioxo-1,4-dihydro-1.sup.6-benzo[1,4]t-
hiazin-3-yl)-isoquinolin-4-ol was prepared in similar fashion
except N-methyl-2-(methylsulfonyl)benzenamine hydrochloride was
substituted for 2-(methylsulfonyl)benzenamine in step 4 to afford
70 mg o(24% theory) IV-2: LCMS RT 3.6 min, M+H.
3-(7-Chloro-4-methyl-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiaz-
in-3-yl)-6-fluoro-1-(4-fluoro-benzyl)-isoquinolin-4-ol was prepared
in similar fashion except
1-chloro-6-fluoro-4-methoxy-isoquinoline-3-carboxylic acid methyl
ester was substituted for
1-chloro-4-methoxy-isoquinoline-3-carboxylic acid methyl ester in
step 3 and 4-chloro-N-methyl-2-(methylsulfonyl)benzenamine was
substituted for 2-(methylsulfonyl)benzenamine hydrochloride in step
4 to afford 7 mg (14% theory) of IV-4: LCMS RT 1.6 min, M+H.
EXAMPLE 9
3-(7-Chloro-4-methyl-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazi-
n-3-yl)-1-(4-fluoro-benzyl)-isoquinolin-4-ol (IV-3)
##STR00024##
2-(5-Chloro-2-methylamino-benzenesulfonyl)-1-[1-(4-fluoro-benzyl)-4-hydro-
xy-isoquinolin-3-yl]-ethanone (36a) was prepared from
1-(4-fluoro-benzyl)-4-methoxy-isoquinoline-3-carboxylic acid methyl
ester and (4-chloro-2-methanesulfonyl-phenyl)-methyl-amine as
described in steps 1-4 of Example 8.
step 1--To a solution of ether 36a (50 mg, 0.073 mmol) in DCM (1
mL) cooled to 0.degree. C. was added a 1.0M BBr.sub.3 solution in
DCM (1.0 mL, 1.0 mmol). The reaction mixture was stirred at RT for
18 h then concentrated in vacuo. Water was added to the residue,
and the resulting solid was collected by filtration and washed with
water and hexanes. The crude material containing 36b was used
directly in the next step.
step 2--To a suspension of a crude product step 1 in EtOH (1 mL)
was added H.sub.2SO.sub.4 (0.041 mL, 0.80 mmol). The reaction
mixture was heated at reflux for 2.5 h then concentrated in vacuo.
Water was added to the residue, and the resulting solid was
collected by filtration and washed sequentially with water, hexanes
and ether to afford 25 mg (65% theory) of 37: LCMS RT 4.4 min,
M+H.
EXAMPLE 10
6-Hydroxy-1,3-diisobutyl-5-(4-methyl-1,1-dioxo-1,4-dihydro-1.lamda..sup.6--
benzo[1,4]thiazin-3-yl)-1H-pyrimidine-2,4-dione
##STR00025##
Sodium hydride (0.054 g, 2.25 mmol, 60% in mineral oil) is added to
a stirred solution of
(4-methyl-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-ac-
etic acid ethyl ester (4, 0.20 g, 0.750 mmol) in dioxane (50 mL)
under an Ar atmosphere. After hydrogen evolution ceases the
solution is stirred for an addition 5 min, 3-methylbutylisocyanate
(0.241 g, 2.43 mmol) is added and the mixture is heated to reflux
for 2 h, is cooled and is poured into 20 mL 1 N HCl and 25 mL of
ice. The solid precipitate is filtered and is purified by flash
chromatography on SiO.sub.2 which affords 38.
EXAMPLE 11
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinoli-
n-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-N-met-
hyl-methanesulfonamide (I-35)
##STR00026##
step 1--To a solution of 40a (0.320 g, 1.28 mmol), DIPEA (0.455 mL,
2.56 mmol) and DCM (15 mL) was added TFAA (1.28 mL, 1.28 mmol, 1.0
M in DCM). The reaction was stirred at RT for 30 min. HPLC
indicated some starting material remained and an addition 2 drops
of TFAA was added. The reaction was stirred for several minutes and
the volatile solvents were removed in vacuo. The crude product was
passed through a SiO.sub.2 plug with 25% EtOAc/hexane and the
solvents were evaporated and the resulting trifluoroacetamide 40b
was used directly in step 2.
step 2--To a solution of 40b (0.420 g, 1.21 mmol) and DMF (12 mL)
were added K.sub.2CO.sub.3 (0.251 g, 1.82 mmol) and methyl iodide
(0.091 mL, 1.46 mmol). The reaction was stirred for 8 h. The
reaction was diluted with 50 mL of water and extracted with
Et.sub.2O. The combined extracts were washed witth water, dried
(MgSO.sub.4), filtered and evaporated to afford 40c
step 3--The trifluoroacetamide 40c (0.430 g, 1.19 mmol) was
dissolved in MeOH (50 mL) and water (20 mL). To this solution was
added K.sub.2CO.sub.3 (1.10 g, 7.95 mmol) and the resulting
solution was stirred at RT for 1 h. The volatile solvents were
removed in vacuo, diluted with water and extracted with EtOAc. The
combined extracts were washed with brine, dried (MgSO.sub.4),
filtered and evaporated to afford 0.260 g of 40d.
step 4--To a solution of 40d (0.260 g 0.984 mmol), DIPEA (0.343 mL,
1.97 mmol) and DCM (20 mL) cooled to 0.degree. C. was added a
solution of mesyl chloride (0.113 g, 0.984 mmol) and DCM. After 5
min no starting material was evident and the reaction was diluted
with water and extracted with EtOAc, The combined extracts were was
with brine, dried (MgSO.sub.4), filtered and evaporated. The crude
product was purified by passing through a plug of SiO.sub.2 eluting
with a EtOAc/hexane gradient (25 to 50% EtOAc) to afford 0.310 g of
40e.
steps 5 to 7--Step 5-7 of the current example were carried out as
described in steps 2-4 of Example 1.
step 8--Using the procedure described in step 5 of Example 1 but
replacing 4 with
[7-(methanesulfonyl-methyl-amino)-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-be-
nzo[1,4]thiazin-3-yl]-acetic acid ethyl ester (43b) there was
obtained
N-{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-N-me-
thyl-methanesulfonamide (I-35: mp 208-212.degree. C., ms
[M+H]=534.1.
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-7-yl}-N-methyl-meth-
anesulfonamide (I-47) was prepared as described above except in
step 8,
1-(2-cyclopropyl-ethyl)-6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione
was replaced by
6-fluoro-1-(4-fluoro-benzyl)-1H-benzo[d][1,3]oxazine-2,4-dione
EXAMPLE 12
3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-3-yl)-1-(2-cy-
clopropyl-ethyl)-4-hydroxy-1H-quinolin-2-one (I-21)
##STR00027##
To a solution of 46 (0.078 g, 0.276 mmol) and anhydrous THF (10 mL)
was added NaH (0.0265 g, 1.11 mmol). After gas evolution ceased the
isatoic anhydride 45 (0.0639 g, 0.276 mmol) was added and the
reaction mixture was heated at reflux. After 5 h the reaction was
complete and several drops of HOAc was added to quench residual NaH
and induce cyclization of the adduct. The reaction mixture was
partitioned between water and EtOAc. The combined extracts were
washed with saturated NaHCO.sub.3 and brine, dried (MgSO.sub.4),
filtered and evaporated. The crude product was purified by
SiO.sub.2 chromatography and eluted with EtOAc/hexane (1:1) to
afford 0.080 g of I-21 as a yellow powder: mp>250.degree. C.; ms
[M+H].sup.+=424.1.
To a solution of I-21 (0.027 g, 0.0612 mmol), DCM (2 mL) and DMF
(0.5 mL) was added methyl isocyanate (MIC, 67.3 .mu.L, 0.0673 mmol,
1M solution in DCM). The resulting solution was stirred in a sealed
tube and progress of the reaction was monitored by hplc. After
several hours the reaction appeared to slow and an additional
aliquot of MIC was added and stirring continued. The reaction
mixture was partitioned between Et.sub.2O and water and the
Et.sub.2O extracts were washed with dil. HCl. Analysis of the
organic extracts indicated the presence of both starting material
and product. A solid precipitated from the aqueous phase which was
collected, washed with Et.sub.2O and dried to afford I-38: mp
220.degree. C. (decomp), [M+H]=499.1.
EXAMPLE 13
3-(7-Amino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-6--
fluoro-1-(4-fluoro-benzyl)-4-hydroxy-1H-quinolin-2-one (I-22),
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-acetamid-
e (I-23) and
N-{3-[6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-
-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methanes-
ulfonamide (I-24)
##STR00028##
step 1--Thiazine 47 (0.300 g, 0.925 mmol) and anhydrous THF (10 mL)
was added NaH (0.185 g, 4.62 mmol). The reaction mixture was warmed
to 75.degree. C. for 15 min to produce a homogenous solution. The
isotoic anhydride 22 (0.265 g, 0.925 mmol) was added and heating
was continued for 1.5 h. The reaction was cooled to RT and HOAc (1
mL) was added and heating at 75.degree. C. resumed for 15 min. The
reaction mixture was diluted with 1N HCl and extracted with EtOAc.
The combined extracts were washed with saturated NaHCO.sub.3 and
brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The
crude product was triturated with toluene and re-evaporated. The
residue was triturated with Et.sub.2O to afford 0.150 g (31%) of
I-23: mp>250.degree. C.; ms [M-H]=522.3.
step 2--A solution of I-23 (0.050 g, 0.0955 mmol) EtOH (10 mL) and
5N NaOH (10 mL) was heated at reflux. The reaction mixture was
cooled to RT and the reaction mixture was concentrated in vacuo.
The residue was neutralized with 1N HCl and extracted with
Et.sub.2O. The combined extracts were washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
triturated with Et.sub.2O, filtered and dried in vacuo to afford
0.045 g of I-22: mp>250.degree. C.; ms [M-H]=480.4.
step 3--To a solution of I-22 (0.100 g, 0.208 mmol) and DCM (15 mL)
was added sequentially DIPEA (0.2684 g, 2.077 mmol) and mesyl
chloride (0.0476 g, 0.415 mmol). The reaction mixture was monitored
by tlc which exhibited a new major spot and several minor
components. The reaction mixture was concentrated in vacuo and
partitioned between EtOAc and 1 N HCl. The EtOAc extract was washed
with brine, dried (MgSO.sub.4), filtered and evaporated. The crude
product was purified by SiO.sub.2 chromatography eluting with
EtOAc. The recovered product was further purified by preparative
tlc to afford I-24: [M-H]=558.2. (Example 7 provides an alternative
route to I-24) The sodium salt I-24a was prepared as described
above for I-9a in Example 1.
EXAMPLE 14
N-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinoli-
n-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-metha-
nesulfonamide, sodium salt (I-28a)
##STR00029##
To a solution of 29b (0.128 g, 0.3552 mmol) and THF (15 mL) was
added NaH (0.0511 g, 2.13 mmol). After stirring for 5 min at RT 45
(0.097 g, 0.39 mmol) was added and the resulting solution heated at
reflux for 3 h. The reaction was quenched with HOAc and partitioned
between water and EtOAc. The organic extracts were washed with
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The crude product was triturated with Et.sub.2O, filtered
and chromatographed on SiO.sub.2 eluting with EtOAc/hexanes (1:1)
to afford I-28 as a yellow solid. The solid was dissolved in MeCN
and 1 equivalent of 0.1M NaOH was added and the reaction stirred
for 1 h. The sodium salt was isolated by lyophilisation of the
aqueous solution to afford I-28a: ms [M+H]=520.1.
Using the same procedure but replacing 29b with
[1,1-dioxo-7-(propane-1-sulfonylamino)-1,4-dihydro-1.lamda..sup.6-benzo[1-
,4]thiazin-3-yl]-acetic acid ethyl ester there was obtained 0.124
mg (62.8%) of propane-1-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-7-yl}-amide
(I-29: mp 145-150.degree. C., ms [M+H]=548.1. The corresponding
sodium salt I-29a was available as described above.
Using the same procedure but replacing 29b with
(7-ethanesulfonylamino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thi-
azin-3-yl)-acetic acid ethyl ester there was obtained 0.0891 g
(41.7%) of ethanesulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-7-yl}-amide
(I-32): mp 140-142.degree. C., ms [M+H]=534.1.
Using the same procedure but replacing 29b with
(7-cyclopropanesulfonylamino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1-
,4]thiazin-3-yl)-acetic acid ethyl ester there was obtained 0.123 g
(58.1%) of cyclopropane-1-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-7-yl}-amide
(I-33): mp 145-155.degree. C., ms [M+H]=546.1.
Using the same procedure but replacing 29b with
[7-(3,5-dimethyl-isoxazole-4-sulfonylamino)-1,1-dioxo-1,4-dihydro-1.lamda-
..sup.6-benzo[1,4]thiazin-3-yl]-acetic acid ethyl ester there was
obtained 0.013 g (9.64%) of 3,5-dimethyl-isoxazole-4-sulfonic acid
{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinolin-
-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-amide
(I-36): mp 150-157.degree. C., ms [M+H]=601.1.
Using the same procedure but replacing 29b with
(7-benzenesulfonylamino-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]th-
iazin-3-yl)-acetic acid ethyl ester there was obtained
N-{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinol-
in-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-benz-
enesulfonamide (I-37): mp>200.degree. C., ms [M+H]=582.1.
EXAMPLE 15
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methoxy-1,1-dioxo-1,4-dihydro--
1.lamda.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one (I-30)
##STR00030##
To a solution of I-18 (0.15 g, 0.311 mmol) and acetone (10 mL) was
added K.sub.2CO.sub.3 (0.86 g, 6.2 mmol) and MeI (0.078 mL, 1.24
mmol) and the resulting mixture was stirred at RT overnight. The
reaction was concentrated in vacuo and the resulting residue
partitioned between water and EtOAc. The organic extracts were
combined, dried (MgSO.sub.4), filter and evaporated. The crude
product was purified by SiO.sub.2 chromatography eluting with a
DCM/EtOAc gradient (0 to 10% EtOAc) to afford 0.060 g of I-30 as a
solid: mp>250.degree. C., ms [M+H]=497.1.
Using the same procedure but replacing methyl iodide with methyl
bromoacetate there was obtained 90 mg (39%) of
{3-[6-fluoro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-y-
l]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yloxy}-acetic
acid methyl ester (I-31: mp 200-207.degree. C., ms [M+H]=555.1.
EXAMPLE 16
3-{3-[1-(2-Cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinoli-
n-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda.6-benzo[1,4]thiazin-7-yloxy}-propion-
amide (I-39)
##STR00031##
Thiazine 47 was prepared as described for I-18 in example 6 except
in step 6, 22 was replaced with
1-(2-cyclopropyl-ethyl)-6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione.
To a solution of 47 (0.13 g, 0.59 mmol) in THF was added NaH (0.026
g, 0.65 mmol) and the solution was stirred for 20 min at RT. To the
solution of the sodium phenolate salt was added acrylamide (0.042
g, 0.59 mmol) and the solution was stirred at RT overnight. The
solution was concentrated in vacuo and the residue partitioned
between 1N HCl and EtOAc. The organic phase was dried (MgSO.sub.4),
filtered and evaporated and the residue purified by SiO.sub.2
chromatography eluting with 4% MeOH/DCM to afford to I-39 which was
approximately 90% pure: ms [M+H]=514.1.
EXAMPLE 17
1-{3-[1-(2-cyclopropyl-ethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-quinoli-
n-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-sulfa-
mide (I-40)
##STR00032##
To a solution of 48 (0.200 g, 0.45 mmol) and DCM (50 mL) at RT was
added dropwise a DCM solution of
N-tert-butyl-chlorosulfonylcarbamate (0.12 g, 0.54 mmol). The
reaction mixture was stirred overnight at RT and the solvent
removed in vacuo and the crude product was purified by SiO.sub.2
chromatography eluting with an acetone/hexane gradient containing
0.5% HCO.sub.2H (10-50% acetone). The purified material was
dissolved in DCM/MeOH (3:1) and TFA (2 mL) was added. The reaction
was stirred at RT overnight and 0.1 mL of water was added and the
reaction was stirred at 50.degree. C. for 4 h. The reaction was
concentrated and DCM (50 mL) was added. The suspension was
sonicated and the solid was filtered and air dried to afford 52 mg
of I-40:
EXAMPLE 18
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H--
pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}--
methanesulfonamide (II-8)
##STR00033##
(7-Nitro-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (49)
was prepared as described in in step 2 of example 7 except ethyl
chloro acetocetate was replaced with methyl chloro
acetoacetate.
step 1--To a mixture of acetone (250 mL) and THF (50 mL) was added
the 49 (5 g, 16.4 mmol) and HCO.sub.2H (7.6 g, 164 mmol). The
mixture was cooled to 2.degree. C. using an ice bath and KMnO.sub.4
(6.5 g, 41 mmol) was added with vigorous stirring. No exotherm was
observed. The reaction was warmed to 10.degree. C. and maintained
there with an 8.degree. C. water bath. A slight exotherm was
observed for approximately 30 min. The reaction was warmed to RT
over 1 h, and stirred for an additional 2 h. The acetone and formic
acid were removed under reduced pressure. Water (200 mL) and EtOAc
(200 mL) were added. The mixture was filtered and the solid was
washed with water and EtOAc. The filtrate was poured into a
separatory funnel and the layers separated. The organic layer was
washed with 1M HCl, saturated NaHCO.sub.3 and brine, dried
(MgSO.sub.4), filtered and evaporated. The product was purified by
column chromatography on SiO.sub.2 eluting with DCM/MeOH to afford
2.75 g (50%) of 50a:LCMS RT 2.26 min, [M+H].
step 2--A solution of 50a (2.75 g, 9.22 mmol) in MeOH (28 mL) and
1N NaOH (28 mL) was stirred at RT for 30 min. The methanol was
removed under reduced pressure, and the mixture was carefully
acidified. The resulting solid was collected, washed with water and
EtOAc, and dried to afford 1.75 g (67%) of 50b: LCMS RT 2.11 min,
does not ionize.
step 3--To a solution of 52a (1.0 g, 4.5 mmol) in DCM (50 mL)
containing 5% HOAc was added 4-fluorobenzaldehyde (0.83 g, 6.7
mmol). This mixture was stirred at RT for 4 h. NaBH(OAc).sub.3
(1.89 g, 8.94 mmol) was added and the mixture stirred at RT for an
additional 1 h. The reaction mixture was evaporated and dissolved
in EtOAc (100 mL). The organic phase was washed with 1N NaOH (100
mL), brine (100 mL), and dried (MgSO.sub.4). The solvent was
removed under reduced pressure to afford 0.73 g (55%) of 52b: LCMS
RT 2.75 min, [M+H].
step 4--To a solution of 50b (0.104 mg, 0.35 mmol) and 52b (0.100
mg. 0.35 mmol) in DMF (20 mL) was added DCC (0.044 mg, 0.35 mmol).
The mixture was stirred at RT for 1 h, poured into 1N HCl (50 mL),
and extracted into EtOAc (100 mL). The organic phase was washed
with brine, dried (MgSO.sub.4), filtered and evaporated to afford
0.20 g (100%) of 53: LCMS RT 3.66 min, [M-H].
step 5--To a suspension of 53 (0.20 mg, 0.35 mmol) in IPA (10 mL)
was added sodium tert-butoxide (0.84 mg, 0.88 mmol). The reaction
mixture was stirred at RT overnight and poured into 1N HCl (20 mL).
The resulting solid was collected, washed with DCM, and the mother
liquid was collected. The organic layer was washed with acidic
brine, dried (MgSO.sub.4), filtered and the solvents evaporated
under reduced pressure. A solid was collected from DCM/hexane to
afford 0.085 g (45%) of 54a: LCMS RT 2.68 min, [M-H].
step 6--The nitro compound 54a (0.51 g, 1.05 mmol) was dissolved in
absolute EtOH (45 mL), and activated Raney Nickel (1 mL, suspension
in water) was added. The reaction flask was thrice purged with
nitrogen. Hydrogen was added and removed three times. The mixture
was rapidly stirred for 30 min under hydrogen balloon. The mixture
was filtered and the solvent was removed under reduced atmosphere
to afford 0.41 g (85%) of 54b: LCMS RT 2.52 min, [M-H].
step 7--A solution of 54b (0.200 g, 0.44 mmol) in pyridine (20 mL)
was cooled to 0.degree. C. Methanesulfonyl chloride (0.100 g, 0.87
mmol) was added and the mixture stirred at 0.degree. C. for 1 h.
The mixture was acidified with 1N HCl, and the product was
extracted into EtOAc. The organics were washed with brine, dried
(MgSO.sub.4), filtered and concentrated under reduced pressure. The
product was purified by column chromatography on SiO.sub.2 eluting
with EtOAc/hexanes, and then re-purified on an SiO.sub.2 column
eluting with DCM/MeOH to afford 70 mg (55%) of II-8: LCMS RT 2.39
min, [M-H].
N-{3-[5-tert-Butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,5-dihyd-
ro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin--
7-yl}-methanesulfonamide was prepared by a similar procedure except
4-fluoro-benzaldehyde was replaced with
4-fluoro-3-methyl-benzaldehyde which afforded II-9.
N-{3-[(S)-5-tert-Butyl-1-(4-fluoro-3-methoxy-benzyl)-4-hydroxy-2-oxo-2,5--
dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thi-
azin-7-yl}-methanesulfonamide was prepared by a similar procedure
except 4-fluoro-benzaldehyde was replaced with
4-fluoro-3-methoxy-benzaldehyde which afforded II-10.
N-{3-[(S)-5-tert-Butyl-1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-d-
ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thia-
zin-7-yl}-methanesulfonamide was prepared by a similar procedure
except 4-fluoro-benzaldehyde was replaced with
3-chloro-4-fluoro-benzaldehyde which afforded II-11.
EXAMPLE 19
1-tert-Butyl-4-(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-y-
l)-2-(4-fluoro-benzyl)-5-hydroxy-1,2-dihydro-pyrazol-3-one
(II-17)
##STR00034##
step 1--To a suspension of 1-tert-butylhydrazine hydrochloride (5.0
g, 40 mmol) in ether (200 mL) was added TEA (5.6 mL, 40 mmol) and
4-fluorobenzaldehyde (5.0 g, 40 mmol). After stirring at RT for 30
min, MgSO.sub.4 (5.8 g, 48 mmol) was added. The resulting reaction
mixture was stirred at RT for 2 days and filtered. The filtrate was
evaporated under reduced pressure to afford 7.0 g (90%) of 56b
which was taken directly into the next step.
step 2--To a solution of the hydrazone 56b (3.97 g, 20.5 mmol) in
EtOAc (100 mL) was added pyridine (1.6 g, 20.5 mmol) followed by
ethyl chloroformate (1.96 mL, 20.5 mmol). After stirring at RT for
1 h, the reaction mixture was filtered. The filtrate was evaporated
under reduced pressure to afford 5.2 g (96%) of 56c which was taken
directly into the next step: LCMS RT 3.8 min, M-(tert-butyl).
step 3--To a solution of the hydrazone 56c (2.0 g, 7.5 mmol) and
MeOH (50 mL) was added 10% Pd/C (80 mg, 0.75 mmol). The reaction
mixture was hydrogenated at RT for 2 h under 1 atm of hydrogen.
After removal of the palladium hydride by filtration, the MeOH was
removed under reduced pressure. The resulting yellow oil was taken
up in EtOAc, washed with water, dried (MgSO.sub.4), filtered and
the solvent was removed under reduced pressure. The product was
purified by column chromatography on SiO.sub.2 eluting with
EtOAc/hexanes to afford 1.6 g (80%) of 57: LCMS RT 3.8 min,
[M+H].
step 4--To a solution of
(1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-acetic
acid (55, 240 mg, 1.0 mmol) and a 1:1 mixture of DCM:DMF (5 mL) was
added DCC (210 mg, 1.0 mmol) followed by hydrazine 57 (228 mg, 0.85
mmol). After stirring for 2 h at RT, the urea by-product was
filtered off and the filtrate concentrated under reduced pressure.
The product was purified by column chromatography on SiO.sub.2
eluting with EtOAc/hexanes to afford 0.052 g (12%) of 58: LCMS RT
3.5 min, [M-H].
step 5--To a solution of 58 (100 mg, 0.20 mmol) in THF (1 mL) was
added NaH (25 mg, 0.61 mmol). The reaction mixture was heated at
reflux for 30 min, quenched with saturated aqueous NH.sub.4Cl and
extracted into EtOAc (2.times.). The combined organics were dried
(Na.sub.2SO.sub.4), filtered and the solvent was removed under
reduced pressure. The product was purified by reverse-phase column
chromatography eluting with MeCN/water to afford 55 mg (61%) of
II-17: LCMS RT 2.2 min, [M-H].
EXAMPLE 20
N-{3-[7-(4-fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3--
b]pyridin-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-y-
l}-methanesulfonamide (I-74)
##STR00035##
step 1--2-Amino-5-methyl-thiophene-3-carboxylic acid methyl ester
(60a, 5.0 g, 29.2 mmol) was placed in a 250 mL round-bottom flask
equipped with a stir bar and suspended in 100 mL of a 3:2:1 mixture
of THF, MeOH and water. Lithium hydroxide monohydrate was dissolved
in 85 mL of water and added to the flask with stirring. The flask
was equipped with a condenser and the mixture was heated at
85.degree. C. for 2 h. After cooling, the THF and MeOH were
evaporated, EtOAc was added, and the organic and aqueous layers
were separated. The aqueous layer was acidified to pH 4 with 1M HCl
and extracted with EtOAc. The organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated to give 4.0 g (87%)
of 2-amino-5-methyl thiophene-3-carboxylic acid (60b) which was
used without purification: ms [M-H]=156.
step 2--A suspension of 60b (4.0 g, 25.5 mmol) and dioxane (65 mL)
was cooled to 5.degree. C. Phosgene (22.5 mL of a 20% solution in
toluene, 45.9 mmol) was added dropwise through a septum. The flask
was equipped with a condenser and the mixture was refluxed for 4 h.
After cooling the solvents were evaporated in vacuo to afford 5.0 g
(100%) of 6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (61a)
which was used without purification: ms [M-H]=182.
step 3--Sodium hydride (1.5 g of a 60% dispersion in mineral oil,
37.5 mmol) was suspended in DMF (50 mL) in a 250 mL round-bottom
flask equipped with a stir bar, and cooled to 0.degree. C. and
maintained under a nitrogen atmosphere. A solution of 61a (4.6 g,
25 mmol) dissolved in DMF (50 mL) was added dropwise through a
septum. The flask was removed from the ice bath and the mixture was
stirred at RT for 30 m. The reaction was cooled to 10.degree. C.
and 1-bromomethyl-4-fluoro-benzene (3.74 mL, 30 mmol) was added
through the septum. The flask was removed from the ice bath and the
mixture was stirred at RT for 2 h. The reaction was poured into ice
and 1N HCl, extracted twice with EtOAc, dried (Na.sub.2SO.sub.4),
filtered and concentrated. A solid was precipitated from the EtOAc
by addition of Et.sub.2O and hexanes to afford 3.0 g (41%) of
1-(4-fluoro-benzyl)-6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione
(61b): ms 2[M+Na]=605.
step 4--A 50 mL RB flask was charged with 50a (387 mg, 1.3 mmol)
and THF (15 mL). The flask was purged with argon, the solution was
cooled to 0.degree. C. and of potassium t-butoxide (1.6 mL of a 1M
solution in THF) was added. The mixture was stirred at RT for 10
min. To the THF solution was added solid
1-(4-fluoro-benzyl)-6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione
(416 mg, 1.4 mmol). The reaction was stirred at RT under argon
overnight. The reaction was quenched by adding HCO.sub.2H (0.5 mL)
and Et.sub.2O (13 mL) was added. The resulting precipitate was
filtered and washed with Et.sub.2O. The mother liquor was
concentrated and precipitated solid was again filtered and washed
with Et.sub.2O. This process was repeated once again to afford 637
mg (95%) of 62 which was used without purification: ms
[M-H]=512.
step 5--To a suspension of 62 (636 mg, 1.24 mmol) and absolute EtOH
(10 mL) was added Sn(II)Cl.sub.2 (1.17 g, 6.2 mmol) and 1M HCl (0.5
mL) and the resulting mixture heated at reflux for 3 h. After
cooling, the EtOH was evaporated and 10 mL each of EtOAc and TEA
were added to the flask. The mixture was stirred at RT for several
min, filtered through CELITE.RTM., and the pad washed with several
portions of EtOAc. The filtrate was concentrated, redissolved in
EtOAc, and filtered again through CELITE.RTM.. The filtrate was
washed with saturated aqueous NaHCO.sub.3, water and brine. The
extracts were dried (Na.sub.2SO.sub.4), concentrated, and
triturated with diethyl ether to afford 208 mg (35%) of I-73 which
was used without further purification: ms [M-H]=482.
step 6--To a suspension of I-73 (208 mg, 0.43 mmol) in pyridine (2
mL) cooled to 0.degree. C. was added solid DMAP (53 mg, 0.43 mmol)
and MeSO.sub.2Cl (67 .mu.L, 0.86 mmol) was added dropwise through a
septum. The reaction was stirred at 0.degree. C. for 30 min. The
pyridine was evaporated and the residue partitioned between EtOAc
and 1M HCl. The organic layer was washed with water and brine,
dried (Na.sub.2SO.sub.4), filtered and concentrated. Preparative
TLC plates were run in 10% MeOH/DCM to remove an undesired higher
molecular weight side product. The remaining material was extracted
from the silica with 10% MeOH/DCM and the solution concentrated.
The residue was dissolved in THF (2 mL) and a solution of NaOH (40
mg in 1 mL of H.sub.2O) was added to hydrolyze a portion of the
crude reaction mixture which was bis-sulfonylated. The solution was
stirred at RT for 2 h, acidified with 1M HCl, extracted with EtOAc,
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue
was triturated with diethyl ether to afford 30 mg (12%) of
N-{3-[7-(4-fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-
-b]pyridin-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7--
yl}-methanesulfonamide (I-74) as a yellow powder: ms [M+H]=562.
Compounds I-43, I-46, I-53, I-56, I-60 and I-61 were prepared as
described in Example 20 except in step 4, 61b was replaced by
6-fluoro-1-(4-fluoro-benzyl)-1H-benzo[d][1,3]oxazine-2,4-dione and
in step 7 methanesulfonyl chloride was replaced by ethylsulfonyl
chloride, n-propylsulfonyl chloride, cyclopropylsulfonyl chloride,
benzylsulfonyl chloride, iso-propylsulfonyl chloride and
n-butylsulfonyl chloride respectively.
EXAMPLE 21
N-{3-[7-(4-fluoro-benzyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-
-5-yl]-1,1-dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-7-yl}-methan-
esulfonamide (I-75)
##STR00036##
1H-thieno[2,3-d][1,3]oxazine-2,4-dione was prepared as described in
Tetrahedron 1998 54:10789-10800 which afforded 1.08 g (64%) of 64a
which was used without further purification: ms [M-H]=168.
1-(4-Fluoro-benzyl)-1H-thieno[2,3-d][1,3]oxazine-2,4-dione was
prepared as described in Tetrahedron 1999 55:6167-7174 except
benzyl bromide was replaced with 1-bromomethyl 4-fluoro-benzene to
afford 850 mg (47%) of 64b which was used without further
purification.
step 3--A 50 mL RB flask was charged with 50a (0.500 g, 1.68 mmol)
and THF (17 mL). The flask was purged with argon and cooled to
0.degree. C. A solution of potassium t-butoxide in THF (2.0 mL of a
1M solution) was added dropwise. The mixture was stirred at RT for
30 min. To the resulting solution was added 64b (464 mg, 1.68
mmol). The reaction was stirred at RT under argon for 24 h. The
reaction was quenched with 0.1 mL of formic acid and 20 mL of
Et.sub.2O was added. The precipitate which formed was filtered and
washed with Et.sub.2O to afford 415 mg (50%) of 65a: ms
[M-H]=498.
step 4--A flask was charged with 65a (400 mg, 0.8 mmol) and 2.0M
ammonia in MeOH (8 mL). The flask was purged thoroughly with argon.
A quantity of Raney nickel was added to the flask with a pipette
and the flask was purged with hydrogen three times. The reaction
was stirred at RT under a hydrogen balloon overnight. After purging
the flask with argon, the reaction mixture was filtered through
filter paper and washed with MeOH and water. The solvents were
evaporated and 1M HCl and EtOAc were added. The layers were
separated and the organic layer was dried (Na.sub.2SO.sub.4),
concentrated and triturated with Et.sub.2O to afford 75 mg (20%) of
65b which was used without purification: ms [M-H]=468.
step 5--To a suspension of 65b (0.069 g, 0.15 mmol) and MeCN (1.5
mL) was added methanesulfonic anhydride (64 mg, 0.36 mmol) and the
reaction was heated at reflux for 2 h, then stirred at RT
overnight. The mixture was partitioned between saturated aqueous
NaHCO.sub.3 and EtOAc. The organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated. Preparative TLC
plates were run in 10% MeOH/DCM. The product was extracted from the
silica with 10% MeOH/DCM, concentrated and triturated with
Et.sub.2O to afford 13 mg (16%) of I-75: ms [M-H]=546.
EXAMPLE 22
##STR00037##
step 1--To a solution of the sulfonyl isocyanate (1.35 g, 9.7 mmol)
in MeCN (10 mL) cooled to 0.degree. C. was added chloroethanol
(0.65 mL, 9.74 mmol) in one portion. The reaction was stirred at
0.degree. C. for 30 min then at RT for an additional 1 h. The MeCN
solution of 69 was used in the next reaction.
step 2--To a solution of the I-22 (0.7 g, 1.5 mmol) in MeCN (100
mL) was added the solution of 69 from step 1 (1.5 mL), followed by
N-methyl morpholine (0.44 g, 4.4 mmol). The reaction was stirred at
RT for 1 h and heated to 50.degree. C. for 4 h. The reaction was
diluted with EtOAc, and the organics washed with brine, dried
(MgSO.sub.4), and concentrated under reduced pressure. The product
was purified by SiO.sub.2 chromatography eluting with
acetone/HCO.sub.2H/hexanes to afford 0.57 g (62%) of I-57: LCMS RT
2.92 min, [M-H].
step 3--To a solution of I-57 (0.050 g, 0.08 mmol) in THF (20 mL)
was added a solution of dimethylamine (0.4 mL, 0.8 mmol) in THF.
The reaction was heated at 140.degree. C. in a sealed tube for 16
h, cooled, and then the solvents removed under reduced pressure.
The crude mixture was purified by HPLC (Horizon): first with a
C.sub.18 column and a linear 5-80% acetonitrile/water gradient (TFA
buffered), and then with a silica column and a linear 0-10%
MeOH/DCM gradient to afford 4.6 mg (9.8%) of I-62: LCMS RT 2.93
min, [M-H].
step 4--I-65 was prepared by the method described in step 2 except
dimethylamine was replaced by pyrrolidine to afford 0.6 mg (1.23%)
of I-65: LCMS RT 3.08 min, [M-H].
EXAMPLE 23
6-Fluoro-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methoxymethyl-1,1-dioxo-1,4-di-
hydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-1H-quinolin-2-one
(I-68)
##STR00038##
step 1--Benzothiazole-6-carboxylic acid (71a, 5.0 g, 27.93 mmol)
was dissolved in DCM (96 mL) and MeOH (32 mL) and cooled to
0.degree. C. A solution of trimethylsilyl-diazomethane (28 mL, 2.0M
in hexane) was added dropwise and the resulting solution was
gradually warmed to RT and stirred overnight. The reaction was
quenched slowly by careful addition of HOAc (2 mL) and stirred for
30 min. The solution was concentrated, diluted with EtOAc and
washed with saturated NaHCO.sub.3 solution. The organic extracts
were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
The crude residue was purified by SiO.sub.2 chromatographed eluting
with 15% EtOAc/hexane to afford 4.44 g (82%) of 71b as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3): 9.15 (s, 1H), 8.68 (m,
1H), 8.16 (m, 2H), 3.97 (s, 3H).
step 2--To a solution of 71b (194 mg, 1.01 mmol) and DCM (4 mL)
cooled to -78.degree. C. was added dropwise DIBAL-H (3.0 mL, 1.0M
in DCM) and the resulting solution was gradually warmed to RT and
stirred overnight. The reaction mixture was cooled to 0.degree. C.,
carefully quenched with a saturated sodium potassium tartrate
solution and stirred for 1 h. The solution was thrice extracted
with DCM and the combined organic extracts were dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude
residue was chromatographed on SiO.sub.2 eluting with 35%
EtOAc/hexane to afford 100 mg (61%) of 71c as a yellow oil (61%):
.sup.1H NMR (300 MHz, CDCl.sub.3): 8.95 (s, 1H), 8.07 (d, 1H, J=8.4
Hz), 7.96 (s, 1H), 7.47 (dd, 1H, J=8.4, 1.7 Hz), 4.84 (s, 2H).
step 3--To an ice-cold solution of 71c (607 mg, 3.68 mmol),
CBr.sub.4 (1.33 g, 4.02 mmol) and DCM (4 mL) was added dropwise a
solution of triphenylphosphine (1.05 g, 4.01 mmol) in DCM (4 mL).
The resulting solution was gradually warmed to RT and stirred
overnight. The crude reaction mixture was concentrated and
chromatographed on SiO.sub.2 eluting with a EtOAc/hexane gradient
(10 to 15% EtOAc) to afford 430 mg (51%)of 71d as white solid:
.sup.1H NMR (300 MHz, CDCl.sub.3): 9.02 (s, 1H), 8.10 (d, 1H, J=8.5
Hz), 7.99 (d, 1H, J=1.8 Hz), 7.55 (1H, dd, J=8.5 Hz, 1.8 Hz), 4.65
(s, 2H).
step 4--A solution of 71d (430 mg, 1.89 mmol) and MeOH (7.5 mL) was
cooled to 0.degree. C. and a solution of sodium methoxide (7.5 mL,
0.5M in methanol) was added dropwise. The resulting solution was
stirred overnight at RT. The reaction mixture was concentrated,
diluted with EtOAc and neutralized with 1N HCl. The organic layer
was separated, dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo to afford 308 mg (91%) of 71e as a tan oil: .sup.1H NMR
(300 MHz, CDCl.sub.3): 8.99 (s, 1H), 8.10 (d, 1H, J=8.4 Hz), 7.94
(m, 1H), 7.47 (dd, 1H, J=8.4 Hz, 1.7 Hz), 4.60 (s, 2H), 3.42 (s,
3H).
step 5--To a solution of 71e (308 mg, 1.676 mmol) and EtOH (5 mL)
was added freshly powdered KOH (228 mg, 4.071 mmol). The solution
was heated at reflux overnight. The solution was cooled to
0.degree. C. and 4-chloro-acetoaceticacid methyl ester (220 .mu.L,
1.900 mmol) was added dropwise via syringe. The resulting solution
was gradually warmed to RT and stirred overnight. The reaction
mixture was concentrated, diluted with EtOAc, and washed with 1N
HCl and brine. The organic extracts were dried (Na.sub.2SO.sub.4)
and concentrated in vacuo. The crude product was purified by
SiO.sub.2 chromatography eluting with a EtOAc/hexane gradient (1%
to 5% EtOAc) to afford 266 mg (60%) of 72 as a colorless oil which
solidified on standing (60%): .sup.1H NMR (300 MHz, CDCl.sub.3):
10.61 (s, 1H), 7.19 (d, 1H, J=1.8 Hz), 7.09 (dd, 1H, J=6.1 Hz, 1.9
Hz), 6.86 (d, 1H, J=8.1 Hz), 4.71 (s, 1H), 4.35 (s, 2H), 3.72 (s,
3H), 3.41 (s, 2H), 3.37 (s, 3H).
step 6--The thiazine ester 72 was oxidized with KMnO.sub.4 as
described in step 1 of example 18 to afford 73: ms [M+H]=298,
[M-H]=296.
step 7--The condensation of 22 and 73 was carried out as described
in example 2 to afford I-68: ms [M+H]=511, [M-H]=509.
EXAMPLE 24
3-(1,1-Dioxo-1,4-dihydro-1.lamda..sup.6-benzo[1,4]thiazin-3-yl)-4-hydroxy--
6-methyl-5-phenyl-1H-pyridin-2-one (III-1)
##STR00039##
step 1--A 100 mL RB flask was charged with 75 (2.5 g, 12.6 mmol),
urethane (1.08 g, 12.1 mmol) and POCl.sub.3 (10 mL). The reaction
was heated to 90.degree. C. for 2.5 h at which time the starting
material undetectable by TLC. The volatiles components were removed
in vacuo (80.degree. C. bath temperature) and the purple residue
was partitioned between toluene (100 mL) and water (100 mL) with
sonication. The aqueous layer was extracted with EtOAc (3.times.100
mL). The combined organic phases were concentrated to afford 1.715
g (70%) of 76a as a light yellow solid: LCMS RT 1.95 min,
[M-H].
step 2--The oxazine-2,6-dione 76a (406 mg, 2 mmol) was weighed into
a 50 mL 1-neck flask and dissolved in DMA (20 mL). The solution was
maintained under a N.sub.2 atmosphere and NaH (80 mg, 2 mmol, 60%
dispersion in mineral oil) was added in one portion. The reaction
mixture was stirred for 20 min after which isoamyl bromide (302 mg,
2 mmol) was added and the resulting mixture was heated to
80.degree. C. overnight. The reaction was then quenched with water
(2 mL), stirred for 20 minutes at RT, then loaded directly to a
SiO.sub.2 column and eluted wit 20% EtOAc/hexanes, to afford 398 mg
(73%) of 76b as a yellow oil: LCMS RT 3.21 min, [M-H].
step 3--To a solution of 76b (91 mg, 0.33 mmol), 4 (89 mg, 0.33
mmol) and THF (3.5 mL) was added in one portion NaH (26 mg, 0.66
mmol) was then added in one portion. After the evolution of N.sub.2
subsided the flask was fitted with a reflux condenser, and heated
to 80.degree. C. under a N.sub.2 atmosphere. The reaction was
subsequently monitored by LCMS. When 76b was not longer detectable
by hplc the reaction was cooled to RT and glacial HOAc (500 .mu.L)
and 1 N HCl (5.0 mL) were added sequentially. The aqueous phase was
then extracted with Et.sub.2O (3.times.50 mL). The combined organic
phases were dried (Na.sub.2SO.sub.4), filtered and concentrated.
The crude was then purified by SiO.sub.2 chromatography eluting
with a EtOAc/hexane gradient (25-40% EtOAc) to afford 61 mg (41%)
of III-1 as a yellow semi-solid: LCMS RT 2.34 min, [M-H].
EXAMPLE 25
Preparation of N-Substituted Isatoic Anhydrides
A. Copper-Catalyzed Displacement
##STR00040##
step 1--To a stirred solution of 78a (5 g, 22.8 mmol) in THF (47
mL) maintained under a N.sub.2 atmosphere was added K.sub.2CO.sub.3
(9.4 g, 68.4 mmol), CuBr (0.25 g, 1.14 mmol); and
p-fluorobenzylamine (3 g, 24 mmol) and the mixture stirred at
60.degree. C. overnight. The reaction was cooled in an ice bath and
a solution of EDTA.2H.sub.2O (0.604 g) and water (22 mL) was added
dropwise via addition funnel. The mixture was stirred at RT for an
additional 0.5 h after which the THF was evaporated. The residual
aqueous solution was cooled to 0.degree. C. and 6N HCl (29 mL) was
added dropwise with vigorous stirring. The resulting heterogeneous
mixture was stirred overnight, the solid was filtered and washed
with copious amounts of H.sub.2O then isooctane. The solid was
dried in vacuo to afford 5.05 g (84%) of 78b.
step 2--To a solution of 78 (0.5 g, 1.9 mmol) in dioxane (5 mL)
under a N.sub.2 atmosphere and cooled to 0.degree. C., was added
dropwise phosgene (5 mL, 20% solution in toluene). The solution was
allowed to stir to RT overnight. The phosgene was evaporated and
EtOAc/hexane (10 mL, 1:4) was added with vigorous stirring.
Stirring was continued overnight and the resulting solid was
filtered, washed with hexane, air dried and recrystallized from
hexane/EtOAc to afford 0.467 g (85%) of 22.
B. N-alkylation
##STR00041##
6-fluoroisatoic anhydride (79, 0.6 g, 3.3 mmol) was dissolved in
anhydrous N,N-dimethylacetamide (16 mL). The solution was stirred
under an N.sub.2 atmosphere and NaH (0.146 g, 3.64 mmol, 60%
dispersion in mineral oil) was added. The mixture was stirred for
10 min and then 4-fluoro-3-methylbenzyl bromide (0.74 g, 3.64 mmol)
was added. The reaction was heated to 70.degree. C. for 2 h, cooled
to RT, and then in an ice bath. The cold reaction mixture was
poured into a cold saturated NH.sub.4Cl solution (100 mL) and
extracted twice with Et.sub.2O/EtOAc (100 mL). The combined ether
solutions were washed with water (30 mL), saturated NaCl solution
and dried (Na.sub.2SO.sub.4). The extracts were filtred and
evaporated and the solid was triturated with 10% Et.sub.2O/hexanes
and vacuum dried to afford 900 mg (90%) of 80: ms [M].sup.+=303;
.sup.1H NMR (300 MHz, DMSO-d.sub.6):.delta. 7.84 ppm (1H, dd,
J=7.4, 3 Hz); 7.37 ppm (1H, m); 7.1 ppm (3H, m); 6.99 ppm (1H, dd,
J.about.9 Hz); 5.22 ppm (2H, s); 2.26 ppm (3H, s).
##STR00042##
6-fluoroisatoic anhydride (79, 0.3 g, 1.65 mmol) was dissolved in
anhydrous DMA (8 mL). The solution was stirred under an N.sub.2
atmosphere and NaH (0.073 g, 1.82 mmol, 60% dispersion in mineral
oil) was added. The mixture was stirred for 10 min and additional
sodium hydride (0.066 g, 1.65 mmol) was added followed by a
solution of 4-(bromomethyl)pyridine hydrobromide (0.46 g, 1.82
mmol) and DMA (10 mL). The reaction was heated to 70.degree. C. for
3 h, cooled to room temperature and finally in an ice bath. The
reaction mixture was poured into a cold saturated NH.sub.4Cl
solution (150 mL) and thrice extracted with EtOAc (75 mL). The
combined organic layers were washed with water (40 mL), brine. The
solution was dried (Na.sub.2SO.sub.4), filtered and evaporated to
afford a solid which was dried in a vacuum then triturated with
Et.sub.2O/hexane (1:2) to afford 300 mg (66%) of 81: ms
[M+H].sup.+=273.
EXAMPLE 26
HCV NS5B RNA Polymerase Activity
The enzymatic activity of HCV NS5B570n-BK is measured as
incorporation of radiolabeled nucleotide monophosphates into acid
insoluble RNA products. Unincorporated radiolabel substrate is
removed by filtration and scintillant is added to the washed and
dried filter plate containing radiolabeled RNA product. The light
emitted by the scintillant is proportional to the amount of RNA
product generated by NS5B570n-BK at the endpoint of the
reaction.
The N-terminally histidine tagged HCV polymerase, derived from HCV
BK strain, genotype 1b (NS5B570n-BK) contains a 21 amino acid
deletion at the C-terminus relative to the full-length HCV
polymerase and is purified from E. coli strain M15. The construct
containing the coding sequence of HCV BK strain amino acid residues
2421-2999 (GenBank accession number M58335) downstream of a Taq
promoter expression cassette was inserted into plasmid constructs.
The plasmid constructs are transformed in E. coli and colonies are
inoculated and grown overnight in 10 L of Terrific broth (Tartoff
and Hobbs) supplemented with 100 .mu.g/mL ampicillin at 37.degree.
C. Protein expression is induced by addition of 1 mM
isopropyl-.beta.-D-thiogalactopyranoside (IPTG), when optical
densities reaches between 1.5 and 3.5 OD.sub.600 and the culture is
then incubated for 16- to 18 h at 22.degree. C. NS5B570n-BK is
purified to homogeneity using a three step protocol including
subsequent column chromatography on Ni-NTA, SP-Sepharose HP and
Superdex 75 resins.
Each 50 .mu.l enzymatic reaction contains 8:4 .mu.g/mL polyA:oligo
U.sub.16 (template:primer), 20 nM or 200 nM NS5B570n-BK enzyme, 1
.mu.Ci of tritiated UTP (Perkin Elmer catalog no. TRK412; specific
activity: 30 to 60 Ci/mmol; stock solution concentration from
7.5.times.10.sup.-5 M to 20.6.times.10.sup.-6 M), 40 mM Tris-HCl pH
8.0, 2 to 40 mM NaCl, 4 mM DTT (dithiothreitol), 4 mM MgCl.sub.2,
and 5 .mu.l of compound serial diluted in DMSO. Reaction mixtures
are assembled in MADVNOB 96-well filter plates (Millipore Co.) and
incubated for 2 h at 30.degree. C. Reactions are stopped by
addition of 10% (v/v) trichloroacetic acid and incubated for 40 min
at 4.degree. C. Reactions are filtered, washed with 8 reaction
volumes of 10% (v/v) trichloroacetic acetic acid, 4 reaction
volumes of 70% (v/v) ethanol, air dried, and 25 .mu.l of
scintillant (Microscint 20, Perkin-Elmer) is added to each reaction
well.
The amount of light emitted from the scintillant is converted to
counts per minute (CPM) on a Topcount.RTM. plate reader
(Perkin-Elmer, Energy Range: Low, Efficiency Mode: Normal, Count
Time: 1 min, Background Subtract: none, Cross talk reduction:
Off).
Data is analyzed with GraphPad.RTM. Prism.RTM. and/or
Microsoft.RTM. Excel.RTM.. The reaction in the absence of enzyme is
used to determine the background signal, which is subtracted from
the enzymatic reactions. Positive control reactions are performed
in the absence of compound, from which the background corrected
activity is set as 100% polymerase activity. All data is expressed
as a percentage of the positive control. The compound concentration
at which the enzyme-catalyzed rate of RNA synthesis is reduced by
50% (IC.sub.50) is calculated by fitting equation (i) to
.times..times..times..times..times..times. ##EQU00001## the data,
where "Y" corresponds to the relative enzyme activity (in %), "%
Min" is the residual relative enzymatic activity at saturating
compound concentration, "% Max" is the maximal relative enzymatic
activity compared to positive control, X corresponds to the
compound concentration, and "S" is the Hill coefficient (or
slope).
Alternatively the assay can be run as described above with the
following modifications. The polyA:oligo U.sub.16 homopolymeric RNA
template:primer is replaced by the heteropolymeric cIRES RNA
template at concentrations of 20 nM or 200 nM. The cIRES RNA
template is derived from the complementary sequence of the Internal
Ribosome Entry site of the HCV genome (nucleotide 1 through 378 at
the 5'-end of the negative strand of the HCV genome (EMBL database
accession number AJ238799). The reaction mixture is supplemented
with 1 .mu.M ATP, CTP, and GTP
EXAMPLE 27
Renilla Luciferase Assay
This assay measures the ability of the compounds of formula I to
inhibit HCV RNA replication, and therefore their potential utility
for the treatment of HCV infections. The assay utilizes a reporter
as a simple readout for intracellular HCV replicon RNA level. The
Renilla luciferase gene was introduced into the first open reading
frame of a replicon construct NK5.1 (Krieger et al., J. Virol.
75:4614), immediately after the internal ribosome entry site (IRES)
sequence, and fused with the neomycin phosphotransferase (NPTII)
gene via a self-cleavage peptide 2A from foot and mouth disease
virus (Ryan & Drew, EMBO Vol 13:928-933). After in vitro
transcription the RNA was electroporated into human hepatoma Huh7
cells, and G418-resistant colonies were isolated and expanded.
Stably selected cell line 2209-23 contain replicative HCV
subgenomic RNA, and the activity of Renilla luciferase expressed by
the replicon reflects its RNA level in the cells. The assay was
carried out in duplicate plates, one in opaque white and one in
transparent, in order to measure the anti-viral activity and
cytotoxicity of a chemical compound in parallel ensuring the
observed activity is not due to decreased cell proliferation.
Renilla luciferase HCV replicon cells (2209-23) cultured in
Dulbecco's MEM (GibcoBRL cat no. 31966-021) with 5% fetal calf
serum (FCS, GibcoBRL cat. no. 10106-169) were plated onto a 96-well
plate at 5000 cells per well, and incubated overnight. Twenty-four
hours later, different dilutions of chemical compounds in the
growth medium were added to the cells, which were then further
incubated at 37.degree. C. for three days. At the end of the
incubation time, the cells in white plates were harvested and
luciferase activity was measured by using Dual-Luciferase reporter
assay system (Promega cat no. E1960). All the reagents described in
the following paragraph were included in the manufacturer's kit,
and the manufacturer's instructions were followed for preparations
of the reagents. The cells were washed twice with 200 .mu.l of
phosphate buffered saline (pH 7.0) (PBS) per well and lysed with 25
.mu.l of 1.times. passive lysis buffer prior to incubation at room
temperature for 20 min. One hundred microliter of LAR II reagent
was added to each well. The plate was then inserted into the LB 96V
microplate luminometer (MicroLumatPlus, Berthold), and 100 .mu.l of
Stop & Glo.RTM. reagent was injected into each well and the
signal measured using a 2-second delay, 10-second measurement
program. IC.sub.50, the concentration of the drug required for
reducing replicon level by 50% in relation to the untreated cell
control value, can be calculated from the plot of percentage
reduction of the luciferase activity vs. drug concentration.
WST-1 reagent from Roche Diagnostic (cat no. 1644807) was used for
the cytotoxicity assay. Ten microliter of WST-1 reagent was added
to each well including wells that contain media alone as blanks.
Cells were then incubated for 1 to 1.5 hours at 37.degree. C., and
the OD value was measured by a 96-well plate reader at 450 nm
(reference filter at 650 nm). Again CC.sub.50, the concentration of
the drug required for reducing cell proliferation by 50% in
relation to the untreated cell control value, can be calculated
from the plot of percentage reduction of the WST-1 value vs. drug
concentration.
TABLE-US-00005 TABLE 5 Compound Polymerase Assay LuciferaseActivity
Number IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) I-24 0.1507.sup.1,
0.067.sup.2, 0.013 0.0055.sup.3 I-20 0.15.sup.1 1.053 I-32
0.22.sup.1, 0.0073.sup.3 0.005 I-40 0.35.sup.1 0.009 I-69
0.0144.sup.3 0.015 II-11 0.0046.sup.3 0.009 .sup.1200 nM polyA:
oligo U.sub.16, .sup.2200 nM cIRES, .sup.320 nM cIRES
EXAMPLE 28
Pharmaceutical compositions of the subject Compounds for
administration via several routes were prepared as described in
this Example.
TABLE-US-00006 Composition for Oral Administration (A) Ingredient %
wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesium stearate
0.5%
The ingredients are mixed and dispensed into capsules containing
about 100 mg each; one capsule would approximate a total daily
dosage.
TABLE-US-00007 Composition for Oral Administration (B) Ingredient %
wt./wt. Active ingredient 20.0% Magnesium stearate 0.5%
Crosscarmellose sodium 2.0% Lactose 76.5% PVP
(polyvinylpyrrolidine) 1.0%
The ingredients are combined and granulated using a solvent such as
methanol. The formulation is then dried and formed into tablets
(containing about 20 mg of active compound) with an appropriate
tablet machine.
TABLE-US-00008 Composition for Oral Administration (C) Ingredient %
wt./wt. Active compound 1.0 g Fumaric acid 0.5 g Sodium chloride
2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulated sugar
25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.)
1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilled water q.s. to
100 mL
The ingredients are mixed to form a suspension for oral
administration.
TABLE-US-00009 Parenteral Formulation (D) Ingredient % wt./wt.
Active ingredient 0.25 g Sodium Chloride q.s. to make isotonic
Water for injection to 100 mL
The active ingredient is dissolved in a portion of the water for
injection. A sufficient quantity of sodium chloride is then added
with stirring to make the solution isotonic. The solution is made
up to weight with the remainder of the water for injection,
filtered through a 0.2 micron membrane filter and packaged under
sterile conditions.
TABLE-US-00010 Suppository Formulation (E) Ingredient % wt./wt.
Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethylene
glycol 4000 24.5%
The ingredients are melted together and mixed on a steam bath, and
poured into molds containing 2.5 g total weight.
TABLE-US-00011 Topical Formulation (F) Ingredients grams Active
compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10
Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy
anisole) 0.01 Water q.s. to 100 mL
All of the ingredients, except water, are combined and heated to
about 60.degree. C. with stirring. A sufficient quantity of water
at about 60.degree. C. is then added with vigorous stirring to
emulsify the ingredients, and water then added q.s. about 100
g.
Nasal Spray Formulations (G)
Several aqueous suspensions containing from about 0.025-0.5 percent
active compound are prepared as nasal spray formulations. The
formulations optionally contain inactive ingredients such as, for
example, microcrystalline cellulose, sodium carboxymethylcellulose,
dextrose, and the like. Hydrochloric acid may be added to adjust
pH. The nasal spray formulations may be delivered via a nasal spray
metered pump typically delivering about 50-100 microliters of
formulation per actuation. A typical dosing schedule is 2-4 sprays
every 4-12 hours.
The features disclosed in the foregoing description, or the
following claims, expressed in their specific forms or in terms of
a means for performing the disclosed function, or a method or
process for attaining the disclosed result, as appropriate, may,
separately, or in any combination of such features, be utilized for
realizing the invention in diverse forms thereof.
The foregoing invention has been described in some detail by way of
illustration and example, for purposes of clarity and
understanding. It will be obvious to one of skill in the art that
changes and modifications may be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
All patents, patent applications and publications cited in this
application are hereby incorporated by reference in their entirety
for all purposes to the same extent as if each individual patent,
patent application or publication were so individually denoted.
* * * * *